Fluorene compound and pharmaceutical use thereof

ABSTRACT

The present invention provides an agent for the prophylactic or treatment of diabetes, diabetic complications, insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, brain ischemia, cerebral apoplexy, pulmonary hypertension, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer, namely, a PDHK inhibitor and the like. A compound represented by the following formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof: 
     
       
         
         
             
             
         
       
     
     wherein each symbol is as defined in the specification.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a fluorene compound and a pharmaceutical use thereof. More particularly, the present invention relates to a compound for the prophylaxis or treatment of diabetes, cardiovascular diseases, hyperlactacidemia and cancer based on activation of pyruvate dehydrogenase (PDH) by inhibition of pyruvate dehydrogenase kinase (PDHK), and use thereof. Furthermore, the present invention relates to a compound for the prophylaxis or treatment of diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), brain ischemia, cerebral apoplexy or pulmonary hypertension, and use thereof.

BACKGROUND OF THE INVENTION

In tissue, for reaction using energy, for example, biosynthesis, active biological transport, muscle contraction etc., the energy is supplied by hydrolysis of adenosine triphosphate (ATP). ATP is produced by oxidation of metabolic fuel which yields much energy, such as glucose and free fatty acids. In oxidative tissues such as muscle, ATP is mostly produced from acetyl-CoA that enters citric acid cycle. Acetyl-CoA is produced by oxidation of glucose via glycolytic pathway or β oxidation of free fatty acid. An enzyme that plays a pivotal role in controlling acetyl-CoA production from glucose is PDH. PDH catalyses the oxidation of pyruvate to acetyl-CoA and carbon dioxide with concomitant reduction of nicotinamide adenine dinucleotide (NAD) to NADH.

PDH is a multienzyme complex consisting of three enzyme components (E1, E2 and E3) and some subunits localized in mitochondria matrix. E1, E2 and E3 are responsible for decarboxylation from pyruvate, production of acetyl-CoA and reduction of NAD to NADH, respectively. Two classes of enzyme having regulatory function are associated with the complex. One is PDHK, which are protein kinases having specificity to PDH. The role thereof is to inactivate E1α subunit of the complex by phosphorylation. The other is PDH phosphatases, which are specific protein phosphatases which activate PDH via dephosphorylation of E1α subunit. The proportion of PDH in its active (dephosphorylated) state is determined by the balance of kinase activity and phosphatase activity. The kinase activity is regulated by relative concentrations of metabolic substrates. For example, the kinase activity is activated by an increase in the NADH/NAD, acetyl-CoA/CoA or ATP/adenosine diphosphate (ADP) ratios, and inhibited by pyruvate.

Four PDHK isoenzymes have been identified in mammalian tissues. Particularly, PDHK2 is expressed in a wide range of tissues including the liver, skeletal muscles and adipose tissues involved in glucose metabolism. Since it shows comparatively high sensitivity to activation by increased NADH/NAD or acetyl-CoA/CoA and inhibition by pyruvate, involvement in a short-term regulation of glucose metabolism is suggested.

In diseases such as insulin-dependent (type 1) diabetes and non-insulin-dependent (type 2) diabetes and the like, oxidation of lipids is increased with a concomitant reduction in utilization of glucose. This is one of the factors causing hyperglycemia. When the oxidative glucose metabolism is reduced in type 1 and type 2 diabetes and obesity, PDH activity is also reduced. It suggests involvement of reduced PDH activity in the reduced utilization of glucose in type 1 and type 2 diabetes. On the contrary, hepatic gluconeogenesis is enhanced in type 1 and type 2 diabetes, which also forms one factor causing hyperglycemia. The reduced PDH activity increases pyruvate concentration, which in turn increases availability of lactate as a substrate for hepatic gluconeogenesis. It suggests possible involvement of reduced PDH activity in the enhanced gluconeogenesis in type 1 and type 2 diabetes. When PDH is activated by inhibition of PDHK, the rate of glucose oxidation is considered to rise. As a result, glucose utilization in the body is promoted and hepatic gluconeogenesis is suppressed, whereby hyperglycemia in type 1 and type 2 diabetes is expected to be improved. Another factor contributing to diabetes is impaired insulin secretion, which is known to be associated with reduced PDH activity in pancreatic β cells. It is also known that sustained hyperglycemia due to diabetes causes complications such as neuropathy, retinopathy, nephropathy, cataract and the like. Thiamine and α-lipoic acid contribute to activation of PDH as coenzymes, and also, they or derivatives thereof have been shown to have a promising effect in the treatment of diabetic complications. Thus, activation of PDH is expected to improve diabetic complications.

Under ischemic conditions, limited oxygen supply reduces oxidation of both glucose and fatty acid oxidation and reduces the amount of ATP produced by oxidative phosphorylation in the tissues. In the absence of sufficient oxygen, ATP level is maintained by promoted anaerobic glycolysis. As a result, lactic acid increases and intracellular pH decreases. Even though the body tries to maintain homeostasis of ion by energy consumption, abnormally low ATP level and disrupted cellular osmolarity lead to cell death. In addition, adenosine monophosphate-activating kinase, activated during ischemia, phosphorylates and thus inactivates acetyl-CoA carboxylase. The levels of total malonyl-CoA in the tissue drop, carnitine palmitoyltransferase-I activity is therefore increased and fatty acid oxidation is favored over glucose oxidation by allowing the transport of acyl-CoA into mitochondria. Oxidation of glucose is capable yielding more ATP per mole of oxygen than is oxidation of fatty acids. Under ischemic conditions, therefore, when energy metabolism becomes glucose oxidation dominant by activation of PDH, the ability to maintain ATP level is considered to be enhanced. In addition, since activation of PDH causes oxidation of pyruvate produced by glycolysis, and reducing production of loactate, the net proton burden is considered to be reduced in ischemic tissues. Accordingly, PDH activation by inhibition of PDHK is expected to protectively act in ischemic diseases such as cardiac muscle ischemia.

A drug that activates PDH by inhibition of PDHK is considered to decrease lactate production since it promotes pyruvate metabolism. Hence, such drug is expected to be useful for the treatment of hyperlactacidemia such as mitochondrial disease, mitochondrial encephalomyopathy and sepsis.

In cancer cells, ATP production by oxidative phosphorylation in mitochondria decreases, and ATP production via the anaerobic glycolysis in cytoplasm increases. PDH activation by inhibition of PDHK is expected to promote oxidative phosphorylation in mitochondria, which will induce apoptosis of cancer cells. Therefore, the mechanism is useful for the treatment of cancer diseases. Pulmonary hypertension is characterized by high blood pressure caused by partial narrowing of the pulmonary artery due to promoted cell proliferation therein. In pulmonary hypertension, therefore, activation of PDH in the pulmonary artery cell is expected to promote oxidative phosphorylation in mitochondria, and induce apoptosis of the pulmonary artery cells. Therefore, the mechanism is useful for the treatment of pulmonary hypertension.

It has been shown that dichloroacetic acid, which is a drug having a PDH activating action, provides promising effects for amelioration of hyperglycemia, treatment of myocardial ischemia, treatment of hyperlactacidemia and treatment of cancer diseases. Moreover, usefulness of dichloroacetic acid for the treatment of cerebral ischemia, cerebral apoplexy or pulmonary hypertension has been shown.

From the foregoing findings, a PDHK inhibitor is considered to be useful for the treatment or prophylaxis of diseases relating to glucose utilization disorder, for example, diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia and hyperlactacidemia. In addition, a PDHK inhibitor is considered to be useful for the treatment or prophylaxis of diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.). Furthermore, a PDHK inhibitor is considered to be useful for the treatment or prophylaxis of diseases caused by limited energy substrate supply to the tissues, for example, cardiac failure, cardiomyopathy, myocardial ischemia, dyslipidemia and atherosclerosis. Additionally, a PDHK inhibitor is considered to be useful for the treatment or prophylaxis of cerebral ischemia or cerebral apoplexy. Moreover, a PDHK inhibitor is considered to be useful for the treatment or prophylaxis of mitochondrial disease, mitochondrial encephalomyopathy, cancer and the like. Also, it is considered to be useful for the treatment or prophylaxis of pulmonary hypertension.

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

The present invention aims to provide an agent for the prophylactic or treatment of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer, namely, a PDHK inhibitor and the like. Moreover, the present invention aims to provide a PDHK inhibitor also useful as an agent for the prophylactic or treatment of diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), brain ischemia, cerebral apoplexy or pulmonary hypertension, and the like.

Means of Solving the Problems

The present inventors have conducted intensive studies in an attempt to develop an agent for the prophylactic or treatment of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy, cancer, diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), brain ischemia, cerebral apoplexy or pulmonary hypertension, which is based on a PDHK inhibitory action and found a fluorene compound having a PDHK inhibitory action, and completed the present invention.

Accordingly, the present invention provides the following.

[1] A compound represented by the following formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof.

wherein,

R^(a) is

(1) a hydrogen atom, or (2) a halogen atom;

R^(b) is

(1) a hydrogen atom, (2) a halogen atom, (3) a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group A, (4) a C₂₋₆ alkenyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C, (5) a C₂₋₆ alkynyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C, (6) a cyano group, (7) —C(═O)—R^(b1) wherein R^(b1) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, (8) —C(═O)—OR^(b2) wherein R^(b2) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, (9) —C(═O)—NR^(b3)R^(b4) wherein R^(b3) and R^(b4) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, (10) —C(═O)—NR^(b5)—OR^(b6) wherein R^(b5) and R^(b6) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, (11) —OR^(b7) wherein R^(b7) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, (12) —NR^(b8)R^(b9) wherein R^(b8) and R^(b9) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, (13) —NR^(b10)—C(═O)—R^(b11) wherein R^(b10) and R^(b11) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, (14) —NR^(b12)—C(═O)—OR^(b13) wherein R^(b12) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, and R^(b13) is a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, (15) —O—C(═O)—NR^(b14)R^(b15) wherein R^(b14) and R^(b15) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, or (16) a group represented by the following formula:

wherein

Y^(b) is

(i) a single bond, (ii) a C₁₋₆ alkylene, (iii) a C₂₋₆ alkenylene, (iv) —O—(CH₂)_(n1)— wherein n1 is an integer of 0, or 1 to 4, (v) —O—(CH₂)_(n2)—C(═O)— wherein n2 is an integer of 0, or 1 to 4,

(vi) —C(═O)—, or

(vii) —NR^(b16)— wherein R^(b16) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B; ring T is (i) a C₆₋₁₀ aryl group, (ii) a C₃₋₁₀ cycloalkyl group, (iii) a C₅₋₁₀ bridged cycloalkyl group, (iv) a monocyclic aromatic heterocyclic group which contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms, or (v) a monocyclic non-aromatic heterocyclic group which contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms, R^(j) are the same or different and each is a substituent selected from the following group D, and p is an integer of 0, or 1 to 4;

R^(c) is

(1) a hydrogen atom, (2) a halogen atom, (3) a C₁₋₆ alkyl group, (4) —C(═O)—OR^(c1) wherein R^(c1) is a hydrogen atom or a C₁₋₆ alkyl group, (5) —OR^(c2) wherein R^(c2) is a hydrogen atom or a C₁₋₆ alkyl group, (6) —NR^(c3)R^(c4) wherein R^(c3) and R^(c4) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group, or (7) —NR^(c5)—C(═O)—R^(c6) wherein R^(c5) and R^(c6) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group;

X^(d) is

(1) a nitrogen atom, or

(2) C—R^(d)

wherein R^(d) is (i) a hydrogen atom, (ii) a halogen atom, (iii) a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group A, (iv) a C₂₋₆ alkenyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C, (v) a C₂₋₆ alkynyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C, (vi) a cyano group, (vii) —C(═O)—R^(d1) wherein R^(d1) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, (viii) —C(═O)—OR^(d2) wherein R^(d2) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, (ix) —C(═O)—NR^(d3)R^(d4) wherein R^(d3) and R^(d4) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, (x) —C(═O)—NR^(d5)—OR^(d6) wherein R^(d5) and R^(d6) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, (xi) —OR^(d7) wherein R^(d7) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, (xii) —NR^(d8)R^(d9) wherein R^(d8) and R^(d9) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, (xiii) —NR^(d10)—C(═O)—R^(d11) wherein R^(d10) and R^(d11) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, (xiv) —NR^(d12)—C(═O)—OR^(d13) wherein R^(d12) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, and R^(d13) is a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, or (xv) a group represented by the following formula:

wherein

Y^(d) is

(I) a single bond, or

(II) —C(═O)—,

ring U is (I) a C₆₋₁₀ aryl group, (II) a C₃₋₁₀ cycloalkyl group, (III) a C₅₋₁₀ bridged cycloalkyl group, (IV) a monocyclic aromatic heterocyclic group which contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms, or (V) a monocyclic non-aromatic heterocyclic group which contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms, R^(k) are the same or different and each is a substituent selected from the following group D, and m is an integer of 0, or 1 to 4; R^(e) are the same or different and each is, (1) a halogen atom, or (2) a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C; and n is an integer of 0, or 1 to 3, provided when X^(d) is C—R^(d), and R^(d) is a hydrogen atom, at least one of R^(a), R^(b) and R^(c) is not a hydrogen atom. Group A is selected from the group consisting of (a) a halogen atom, (b) a cyano group, (c) —C(═O)—R^(A1) wherein R^(A1) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, (d) —C(═O)—OR^(A2) wherein R^(A2) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, (e) —C(═O)—NR^(A3)R^(A4) wherein R^(A3) and R^(A4) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, (f) —C(═O)—NR^(A5)—OR^(A6) wherein R^(A5) and R^(A6) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, (g) —OR^(A7) wherein R^(A7) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, (h) —NR^(A8)R^(A9) wherein R^(A8) and R^(A9) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, (i) —NR^(A10)—C(═O)—R^(A11) wherein R^(A10) and R^(A11) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, (j) —NR^(A12)—C(═O)—OR^(A13) wherein R^(A12) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, and R^(A13) is a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, (k) —S(═O)₂—R^(A14) wherein R^(A14) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, (l) —S(═O)₂—OR^(A15) wherein R^(A15) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group B, and

(m) —Si—(CH₂—CH₃)₃.

Group B is selected from the group consisting of (a) a halogen atom, (b) a cyano group, (c) —C(═O)—R^(B1) wherein R^(B1) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C, (d) —C(═O)—OR^(B2) wherein R^(B2) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C, (e) —C(═O)—NR^(B3)R^(B4) wherein R^(B3) and R^(B4) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C, (f) —C(═O)—NR^(B5)—OR^(B6) wherein R^(B5) and R^(B6) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C, (g) —OR^(B7) wherein R^(B7) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C, (h) —NR^(B8)R^(B9) wherein R^(B8) and R^(B9) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C, (i) —NR^(B10)—C(═O)—R^(B11) wherein R^(B10) and R^(B11) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C, (j) —NR^(B12)—S(═O)₂—R^(B13) wherein R^(B12) and R^(B13) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C, (k) —NR^(B14)—C(═O)—OR^(B15) wherein R^(B14) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C, and R^(B15) is a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C, (l) —S(═O)₂—R^(B16) wherein R^(B16) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C, and (m) —S(═O)₂—OR^(B17) wherein R^(B17) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group C. Group C is selected from the group consisting of (a) a halogen atom, (b) —C(═O)—R^(C1) wherein R^(C1) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 halogen atoms, (c) —C(═O)—OR^(C2) wherein R^(C2) is a hydrogen atom or a C₁₋₆ alkyl group, and (d) —OR^(C3) wherein R^(C3) is a hydrogen atom or a C₁₋₆ alkyl group. Group D is selected from the group consisting of (a) a halogen atom, (b) a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E, (c) a C₁₋₆ alkyl group substituted by a C₆₋₁₀ aryl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, (d) a C₁₋₆ alkyl group substituted by a C₃₋₁₀ cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from the following group F, (e) a C₁₋₆ alkyl group substituted by a C₅₋₁₀ bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from the following group F, (f) a C₁₋₆ alkyl group substituted by a monocyclic aromatic heterocyclic group optionally substituted by the same or different 1 to 5 C₁₋₆ alkyl groups (the monocyclic aromatic heterocyclic group contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms), (g) a C₃₋₁₀ cycloalkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, (h) a C₅₋₁₀ bridged cycloalkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, (i) a cyano group, (j) —C(═O)—R^(D1) wherein R^(D1) is a hydrogen atom, a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected frau the following group E, or a monocyclic non-aromatic heterocyclic group optionally substituted by the same or different 1 to 5 substituents selected from the following group F (the monocyclic non-aromatic heterocyclic group contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms), (k) —C(═O)—OR^(D2) wherein R^(D2) is a hydrogen atom, or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E, (l) —C(═O)—NR^(D3)R^(D4) wherein R^(D3) and R^(D4) are the same or different and each is a hydrogen atom, or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E, (m) —C(═O)—NR^(D5)—OR^(D6) wherein R^(D5) and R^(D6) are the same or different and each is a hydrogen atom, or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E, (n) —OR^(D7) wherein R^(D7) is a hydrogen atom, or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E, (o) —NR^(D8)R^(D9) wherein R^(D8) and R^(D9) are the same or different and each is a hydrogen atom, or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E, (p) —NR^(D10)—C(═O)—R^(D11) wherein R^(D10) and R^(D11) are the same or different and each is a hydrogen atom, or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E, (q) —NR^(D12)—C(═O)—OR^(D13) wherein R^(D12) is a hydrogen atom, or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E, and R^(D13) is a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E, (r) —S(═O)₂—R^(D14) wherein R^(D14) is a hydrogen atom, or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E, and (s) —S(═O)₂—OR^(D15) wherein R^(D15) is a hydrogen atom, or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group E. Group E is selected from the group consisting of (a) a halogen atom, (b) a cyano group, (c) —C(═O)—R^(E1) wherein R^(E1) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, (d) —C(═O)—OR^(E2) wherein R^(E2) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, (e) —C(═O)—NR^(E3)R^(E4) wherein R^(E3) and R^(E4) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, (f) —C(═O)—NR^(E5)—OR^(E6) wherein R^(E5) and R^(E6) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, (g) —OR^(E7) wherein R^(E7) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, (h) —NR^(E8)R^(E9) wherein R^(E8) and R^(E9) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, (i) —NR^(E10)—C(═O)—R^(E11) wherein R^(E10) and R^(E11) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, (j) —NR^(E12)—C(═O)—OR^(E13) wherein R^(E12) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, and R^(E13) is a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, (k) —S(═O)₂—R^(E14) wherein R^(E14) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, (l) —S(═O)₂—OR^(E15) wherein R^(E15) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, and (m) —NR^(E16)—S(═O)₂—R^(E17) wherein R^(E16) and R^(E17) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group. Group F is selected from the group consisting of (a) —(CH₂)_(nF1)—C(═O)—OR^(F1) wherein R^(F1) is a hydrogen atom or a C₁₋₆ alkyl group, and nF1 is an integer of 0, or 1 to 4, and (b) —(CH₂)_(nF2)—OR^(F2) wherein R^(F2) is a hydrogen atom or a C₁₋₆ alkyl group, and nF2 is an integer of 0, or 1 to 4. [2] The compound of the above-mentioned [1], wherein X^(d) is C—R^(d) wherein R^(d) is as defined in the above-mentioned [1], or a pharmaceutically acceptable salt thereof, or a solvate thereof. [3] The compound of the above-mentioned [1] or [2], which is represented by the following formula [II], or a pharmaceutically acceptable salt thereof, or a solvate thereof.

wherein each symbol is as defined in the above-mentioned [1]. [4] The compound of the above-mentioned [3], wherein ring U is a monocyclic aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof, or a solvate thereof. [5] The compound of the above-mentioned [3], wherein Y^(d) is a single bond, or a pharmaceutically acceptable salt thereof, or a solvate thereof. [6] The compound of the above-mentioned [4], which is represented by the following formula [III], or a pharmaceutically acceptable salt thereof, or a solvate thereof.

wherein

R^(m) is

(1) a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E, (2) a C₁₋₆ alkyl group substituted by a C₆₋₁₀ aryl group optionally substituted by the same or different 1 to 5 substituents selected from group F, (3) a C₁₋₆ alkyl group substituted by a C₃₋₁₀ cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (4) a C₁₋₆ alkyl group substituted by a C₅₋₁₀ bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (5) a C₁₋₆ alkyl group substituted by a monocyclic aromatic heterocyclic group optionally substituted by the same or different 1 to 5 C₁₋₆ alkyl groups (the monocyclic aromatic heterocyclic group contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms), (6) a C₃₋₁₀ cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, or (7) a C₅₋₁₀ bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, and other symbols are as defined in the above-mentioned [1]. [7] The compound of the above-mentioned [6], wherein R^(m) is (1) a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E′, (2) a C₁₋₆ alkyl group substituted by a C₃₋₁₀ cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (3) a C₁₋₆ alkyl group substituted by a C₅₋₁₀ bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (4) a C₃₋₁₀ cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, or (5) a C₅₋₁₀ bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, and group E′ is selected from the group consisting of (a) a halogen atom, (b) a cyano group, (c) —C(═O)—R^(E1) wherein R^(E1) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, (d) —C(═O)—OR^(E2) wherein R^(E2) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, (e) —C(═O)—NR^(E3)R^(E4) wherein R^(E3) and R^(E4) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, (f) —C(═O)—NR^(E5)—OR^(E6) wherein R^(E5) and R^(E6) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, (g) —OR^(E7) wherein R^(E7) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, (h) —NR^(E8)R^(E9) wherein R^(E8) and R^(E9) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, (i) —NR^(E10)—C(═O)—R^(E11) wherein R^(E10) and R^(E11) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, (j) —NR^(E12)—C(═O)—OR^(E13) wherein R^(E12) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, and R^(E13) is a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, (k) —S(═O)₂—R^(E14) wherein R^(E14) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, and (l) —S(═O)₂—OR^(E15) wherein R^(E15) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from the following group F, or a pharmaceutically acceptable salt thereof, or a solvate thereof. [8] The compound of the above-mentioned [7], which is represented by the following formula [III-A], or a pharmaceutically acceptable salt thereof, or a solvate thereof.

wherein each symbol is as defined in the above-mentioned [7]. [9] The compound of the above-mentioned [7], wherein R^(c) is a hydrogen atom, or a pharmaceutically acceptable salt thereof, or a solvate thereof. [10] The compound of the above-mentioned [7], wherein R^(b) is (1) a hydrogen atom, (2) a halogen atom, (3) a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group A, (4) a C₂₋₆ alkenyl group optionally substituted by the same or different 1 to 5 substituents selected from group C, (5) a C₂₋₆ alkynyl group optionally substituted by the same or different 1 to 5 substituents selected from group C, (6) a cyano group, (7) —C(═O)—R^(b1) wherein R^(b1) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (8) —C(═O)—OR^(b2) wherein R^(b2) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (9) —C(═O)—NR^(b3)R^(b4) wherein R^(b3) and R^(b4) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (10) —C(═O)—NR^(b5)—OR^(b6) wherein R^(b5) and R^(b6) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (11) —OR^(b7) wherein R^(b7) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (12) —NR^(b8)R^(b9) wherein R^(b8) and R^(b9) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (13) —NR^(b10)—C(═O)—R^(b11) wherein R^(b10) and R^(b11) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (14) —NR^(b12)—C(═O)—OR^(b13) wherein R^(b12) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, and R^(b13) is a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, or (15) —O—C(═O)—NR^(b14)R^(b15) wherein R^(b14) and R^(b15) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, or a pharmaceutically acceptable salt thereof, or a solvate thereof. [11] The compound of the above-mentioned [7], wherein R^(a) is a hydrogen atom, or a pharmaceutically acceptable salt thereof, or a solvate thereof. [12] The compound of the above-mentioned [7], wherein n is 0, or a pharmaceutically acceptable salt thereof, or a solvate thereof. [13] The compound of the above-mentioned [7], wherein R^(m) is (1) a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from (i) —C(═O)—OR^(E2) wherein R^(E2) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F, (ii) —C(═O)—NR^(E3)R^(E4) wherein R^(E3) and R^(E4) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F, (iii) —OR^(E7) wherein R^(E7) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F, and (iv) —NR^(E12)—C(═O)—R^(E13) wherein R^(E12) and R^(E13) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F, (2) a C₃₋₁₀ cycloalkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F, or (3) a C₅₋₁₀ bridged cycloalkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F, or a pharmaceutically acceptable salt thereof, or a solvate thereof. [14] The compound of the above-mentioned [7], wherein R^(m) is (1) a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from (i) —C(═O)—OR^(E2) wherein R^(E2) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F, and (ii) —OR^(E7) wherein R^(E7) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F, (2) a C₃₋₁₀ cycloalkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F, or (3) a C₅₋₁₀ bridged cycloalkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F, or a pharmaceutically acceptable salt thereof, or a solvate thereof. [15] The compound of the above-mentioned [4], which is represented by the following formula [VI], or a pharmaceutically acceptable salt thereof, or a solvate thereof.

wherein each symbol is as defined in the above-mentioned [4]. [16] The compound of the above-mentioned [1], which is represented by the following formula, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[17] The compound of the above-mentioned [1], which is represented by the following formula, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[18] A pharmaceutical composition comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier. [19] A PDHK inhibitor comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof. [20] A PDH activator comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof. [21] A PDHK2 inhibitor comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof. [22] A blood glucose level-lowering agent comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof. [23] A lactate level-lowering agent comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof. [24] An agent for the treatment or prophylaxis of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer, comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof. [25] An agent for the treatment or prophylaxis of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, brain ischemia, cerebral apoplexy, pulmonary hypertension, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer, comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof. [26] A method of inhibiting PDHK in a mammal, comprising administering a pharmaceutically effective amount of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal. [27] A method of activating PDH in a mammal, comprising administering a pharmaceutically effective amount of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal. [28] A method of inhibiting PDHK2 in a mammal, comprising administering a pharmaceutically effective amount of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal. [29] A method of decreasing the blood glucose level in a mammal, comprising administering a pharmaceutically effective amount of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal. [30] A method of decreasing lactate level in a mammal, comprising administering a pharmaceutically effective amount of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal. [31] A method for the treatment or prophylaxis of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer in mammal, comprising administering a pharmaceutically effective amount of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal. [32] A method for the treatment or prophylaxis of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, brain ischemia, cerebral apoplexy, pulmonary hypertension, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer in mammal, comprising administering a pharmaceutically effective amount of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal. [33] Use of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof for the production of a PDHK inhibitor. [34] Use of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof for the production of a PDH activator. [35] Use of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof for the production of a PDHK2 inhibitor. [36] Use of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof for the production of a blood glucose level-lowering agent. [37] Use of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof for the production of a lactate level-lowering agent. [38] Use of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof for the production of an agent for the treatment or prophylaxis of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer. [39] Use of the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof for the production of an agent for the treatment or prophylaxis of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, brain ischemia, cerebral apoplexy, pulmonary hypertension, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer. [40] A commercial kit comprising (a) a pharmaceutical composition comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof as active ingredient, and (b) a written matter stating that the pharmaceutical composition can or should be used for the treatment or prophylaxis of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, brain ischemia, cerebral apoplexy, pulmonary hypertension, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer. [41] A commercial package comprising (a) a pharmaceutical composition comprising the compound of any one of the above-mentioned [1] to [17], or a pharmaceutically acceptable salt thereof, or a solvate thereof as active ingredient, and (b) a written matter stating that the pharmaceutical composition can or should be used for the treatment or prophylaxis of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, brain ischemia, cerebral apoplexy, pulmonary hypertension, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer.

Effect of the Invention

Since the fluorene compound of the present invention effectively inhibits the PDHK activity, and further, has preferable properties as a drug such as chemical stability and the like, it is effective as an agent for the prophylaxis or treatment of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer, and the like. Furthermore, the fluorene compound of the present invention is also effective as an agent for the prophylaxis or treatment of diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), brain ischemia, cerebral apoplexy or pulmonary hypertension.

Embodiment of the Invention

The present invention is explained in detail in the following.

The definitions of the terms used in the present specification are as follows.

The “optionally substituted” includes both being substituted at substitutable position(s) of an object group and being unsubstituted. Here, the “unsubstituted” means that all substitutable positions of an object group are occupied by hydrogen atoms.

For example, a “C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group A” means both when the substitutable position(s) of a C₁₋₆ alkyl group is(are) substituted by the same or different 1 to 5 substituents selected from group A, and is(are) not substituted (unsubstituted).

Examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.

The “C₁₋₆ alkyl group” means a straight chain or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. Examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a 1-ethylpropyl group, a hexyl group, an isohexyl group, a 1,1-dimethylbutyl group, a 2,2-dimethylbutyl group, a 3,3-dimethylbutyl group, a 2-ethylbutyl group and the like. Preferred are a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a hexyl group, an isohexyl group, a 3,3-dimethylbutyl group and the like.

The “C₂₋₆ alkenyl group” means a linear or branched chain unsaturated hydrocarbon group having 2 to 6 a carbon atoms and containing one or more double bonds. Examples thereof include a vinyl group, a 1-methylvinyl group, a 1-propenyl group, an allyl group, a methylpropenyl group (1-methyl-1-propenyl group, 2-methyl-1-propenyl group etc.), a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, a methylbutenyl group (1-methyl-1-butenyl group, a 2-methyl-1-butenyl group, a 3-methyl-1-butenyl group etc.), a pentenyl group, a methylpentenyl group, a hexenyl group and the like. Preferred are a vinyl group, a 1-methylvinyl group, a 1-propenyl group, a methylpropenyl group and the like.

The “C₂₋₆ alkynyl group” means a linear or branched chain unsaturated hydrocarbon group having 2 to 6 a carbon atoms and containing one or more triple bonds. Examples thereof include an ethynyl group, a propynyl group (1-propynyl group, 2-propynyl group), a butynyl group, a pentynyl group, a hexynyl group and the like. Preferred are an ethynyl group, a 1-propynyl group and the like.

The “C₁₋₆ alkylene” means a divalent group derived from the above-mentioned “C₁₋₆ alkyl group”. Examples thereof include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and the like. Preferred are methylene, ethylene, trimethylene and the like.

The “C₂₋₆ alkenylene” means a divalent group derived from the above-mentioned “C₂₋₆ alkenyl group”. Examples thereof include vinylene, propenylene, butenylene, pentenylene, hexenylene and the like. Preferred are vinylene and the like.

The “C₆₋₁₀ aryl group” means an aromatic hydrocarbon group having 6 to 10 carbon atoms. Examples thereof include a phenyl group, a 1-naphthyl group, a 2-naphthyl group and the like. Preferred is a phenyl group.

The “C₃₋₁₀ cycloalkyl group” means a monocycle saturated hydrocarbon group having 3 to 10 carbon atoms. Examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group and the like. Particularly, a C₃₋₆ cycloalkyl group (e.g., a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group etc.) is preferable.

The “C₅₋₁₀ bridged cycloalkyl group” means a bridged cyclic saturated hydrocarbon group having 5 to 10 carbon atoms. Examples thereof include a bicyclopentanyl group, a bicyclohexyl group, a bicycloheptyl group, a tricycloheptyl group, a bicyclooctyl group, an adamantyl group and the like. Particularly, an adamantyl group is preferable.

The “monocyclic aromatic heterocyclic group” means a monocyclic aromatic heterocyclic group, containing, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and having 3 to 7 ring-constituting atoms. Examples thereof include a furyl group, a thienyl group, a pyrrolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, an imidazolyl group, a pyrazolyl group, an oxadiazolyl group (1,2,5-oxadiazolyl group, 1,3,4-oxadiazolyl group, 1,2,4-oxadiazolyl group), a thiadiazolyl group (1,2,5-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,4-thiadiazolyl group), a triazolyl group (1,2,3-triazolyl group, 1,2,4-triazolyl group), a tetrazolyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazinyl group, a triazinyl group and the like. Preferred are a thienyl group, an oxazolyl group, a thiazolyl group, an imidazolyl group, a pyrazolyl group, an oxadiazolyl group (1,3,4-oxadiazolyl group, 1,2,4-oxadiazolyl group), a triazolyl group (1,2,4-triazolyl group), a tetrazolyl group, a pyridyl group, a pyrimidinyl group and the like.

The “monocyclic non-aromatic heterocyclic group” means a monocyclic saturated or partially unsaturated heterocyclic group, which contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms. Examples thereof include an oxiranyl group, a thioranyl group, an aziridinyl group, an azetidinyl group, an oxetanyl group, a pyrrolidinyl group, a pyrrolidino group (1-pyrrolidinyl group), a tetrahydrofuranyl group, a tetrahydrothienyl group, an oxazolinyl group, an oxazolidinyl group, an isoxazolinyl group, an isoxazolidinyl group, a thiazolinyl group, a thiazolidinyl group, an isothiazolinyl group, an isothiazolidinyl group, an imidazolinyl group, an imidazolidinyl group, a pyrazolinyl group, a pyrazolidinyl group, a piperidinyl group, a piperidino group (1-piperidinyl group), a morpholinyl group, a morpholino group (4-morpholinyl group), a thiomorpholinyl group, a thiomorpholino group (4-thiomorpholinyl group), a piperazinyl group, a piperazino group (1-piperazinyl group), a hexahydro-1,3-oxazinyl group and the like. The group may have 1 or 2 oxo groups. In addition, when the group contains a sulfur atom as a hetero atom, the sulfur atom may be mono- or dioxide.

Particularly, an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a 2-oxopyrrolidinyl group, a 2-oxopyrrolidino group, an oxazolidinyl group, a 2-oxooxazolidinyl group, an isothiazolidinyl group, a 1,1-dioxoisothiazolidinyl group, an imidazolidinyl group, a 2-oxoimidazolidinyl group, a 2-oxopiperidinyl group, a 2-oxopiperidino group, a morpholinyl group, a morpholino group, a 2-oxomorpholino group, a piperazinyl group, a piperazino group, a 2-oxopiperazino group, a hexahydro-2-oxo-1,3-oxazinyl group and the like are preferable.

The “—C(═O)—NR^(b3)R^(b4) wherein R^(b3) and R^(b4) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B” in the specification is represented by the following formula

wherein R^(b3) and R^(b4) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B.

Specific examples thereof include

Furthermore, the “—C(═O)—NR^(b5)—OR^(b6) wherein R^(b5) and R^(b6) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B” is represented by the following formula

wherein R^(b5) and R^(b6) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B.

Specific examples thereof include

Preferable embodiment of each group of the compound represented by the formula [I] (hereinafter to be sometimes abbreviated as compound [I]) is explained in the following.

R^(a)

R^(a) is (1) a hydrogen atom, or (2) a halogen atom, preferably, a hydrogen atom, a fluorine atom or a chlorine atom, more preferably, a hydrogen atom.

R^(b)

Preferable embodiments of R^(b) are classified into the following type A and type B.

[Type A]

A type wherein R^(b) is a group represented by the following formula:

wherein each symbol is as defined above. When X^(d) is C—R^(d), compound [I] is represented by the formula [IV]

[Type B]

A type wherein R^(b) is

(1) a hydrogen atom, (2) a halogen atom, (3) a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group A, (4) a C₂₋₆ alkenyl group optionally substituted by the same or different 1 to 5 substituents selected from group C, (5) a C₂₋₆ alkynyl group optionally substituted by the same or different 1 to 5 substituents selected from group C, (6) a cyano group, (7) —C(═O)—R^(b1) wherein R^(b1) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (8) —C(═O)—OR^(b2) wherein R^(b2) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (9) —C(═O)—NR^(b3)R^(b4) wherein R^(b3) and R^(b4) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (10) —C(═O)—NR^(b5)—OR^(b6) wherein R^(b5) and R^(b6) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (11) —OR^(b7) wherein R^(b7) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (12) —NR^(b8)R^(b9) wherein R^(b8) and R^(b9) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (13) —NR^(b10)—C(═O)—R^(b11) wherein R^(b10) and R^(b11) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (14) —NR^(b12)—C(═O)—OR^(b13) wherein R^(b12) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, and R^(b13) is a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, or (15) —O—C(═O)—NR^(b14)R^(b15) wherein R^(b14) and R^(b15) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B.

Preferable embodiments of type A and type B are explained in the following.

[Type A]

As Y^(b), preferred is

(i) a single bond, (ii) a C₁₋₃ alkylene (particularly, methylene, trimethylene), (iii) a C₂₋₃ alkenylene (particularly, vinylene), (iv) —O—(CH₂)_(n1)— wherein n1 is an integer of 0, or 1 to 4 (particularly, 0, or 1 to 3), (v) —O—(CH₂)_(n2)—C(═O)— wherein n2 is an integer of 0, or 1 to 4 (particularly, 1),

(vi) —C(═O)—, or

(vii) —NR^(b16)— wherein R^(b16) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group); more preferably, a single bond, —O—CH₂—, —O—(CH₂)₂—, —O—CH₂—C(═O)—, or —C(═O)—.

As ring T, preferred is

(i) a C₆₋₁₀ aryl group, (ii) a C₃₋₆ cycloalkyl group, (iii) a C₅₋₁₀ bridged cycloalkyl group, (iv) a monocyclic aromatic heterocyclic group which contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and 5 or 6 ring-constituting atoms, or (v) a monocyclic non-aromatic heterocyclic group which contains, besides carbon atom, 1 or 2 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and 3 or 6 ring-constituting atoms; more preferred is (i) a phenyl group, (ii) a C₃₋₆ cycloalkyl group (particularly, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group), (iii) an adamantyl group, (iv) a monocyclic aromatic heterocyclic group selected from a thiazolyl group, a pyridyl group, a thienyl group, an oxazolyl group, a 1,2,4-oxadiazolyl group, a pyrazolyl group, a tetrazolyl group, and a pyrimidinyl group, or (v) a monocyclic non-aromatic heterocyclic group selected from a piperidino group, a pyrrolidino group, an azetidinyl group, an aziridinyl group, a morpholino group, a piperazino group, a 2-oxopyrrolidino group, a 2-oxopiperidino group, a 2-oxopyrrolidin-5-yl group, a 2-oxo-1,3-oxazolidin-3-yl group, a 3-oxomorpholino group, a 1,1-dioxoisothiazolidinyl group, a 2-oxoimidazolidinyl group and a hexahydro-2-oxo-1,3-oxazinyl group.

R^(j) is preferably,

(1) a halogen atom, (2) a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E, (3) a C₁₋₆ alkyl group substituted by a C₃₋₁₀ cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (4) a cyano group, (5) —C(═O)—R^(D1) wherein R^(D1) is a hydrogen atom, a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E, or a monocyclic non-aromatic heterocyclic group optionally substituted by the same or different 1 to 5 substituents selected from group F (the monocyclic non-aromatic heterocyclic group contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms), (6) —C(═O)—OR^(D2) wherein R^(D2) is a hydrogen atom, or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E, (7) —C(═O)—NR^(D3)R^(D4) wherein R^(D3) and R^(D4) are the same or different and each is a hydrogen atom, or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E, (8) —OR^(D7) wherein R^(D7) is a hydrogen atom, or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E, (9) —NR^(D8)R^(D9) wherein R^(D8) and R^(D9) are the same or different and each is a hydrogen atom, or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E, or (10) —NR^(D10)—C(═O)—R^(D11) wherein R^(D10) and R^(D11) are the same or different and each is a hydrogen atom, or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E, more preferably, (1) a halogen atom (particularly, a fluorine atom, a chlorine atom), (2) a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a tert-butyl group, a neopentyl group) optionally substituted by the same or different 1 to 5 substituents selected from group E (particularly, a hydroxy group, a methoxymethoxy group, a carboxyl group, a carbamoyl group), (3) a C₁₋₆ alkyl group substituted by a C₃₋₁₀ cycloalkyl (particularly, a cyclohexylmethyl group), (4) a cyano group, (5) —C(═O)—R^(D1) wherein R^(D1) is a hydrogen atom, a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group), or a monocyclic non-aromatic heterocyclic group which contains besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms (particularly, a pyrrolidino group, a piperidino group, a 4-hydroxypiperidino group, a 3-hydroxypyrrolidino group), (6) —C(═O)—OR^(D2) wherein R^(D2) is a hydrogen atom, or a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group), (7) —C(═O)—NR^(D3)R^(D4) wherein R^(D3) and R^(D4) are the same or different and each is a hydrogen atom, or a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group), (8) —OR^(D7) wherein R^(D7) is a hydrogen atom, or a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group, a propyl group) optionally substituted by the same or different 1 to 5 substituents selected from group E (particularly, a methoxy group, a carboxy group, a hydroxy group, a methoxycarbonyl group, a carbamoyl group, a methylcarbamoyl group, a dimethylcarbamoyl group), (9) —NR^(D8)R^(D9) wherein R^(D8) and R^(D9) are the same or different and each is a hydrogen atom, or a C₁₋₆ alkyl group (particularly, a methyl group), or (10) —NR^(D10)—C(═O)—R^(D11) wherein R^(D10) and R^(D11) are the same or different and each is a hydrogen atom, or a C₁₋₆ alkyl group (particularly, a methyl group).

Specifically preferable examples of R^(j) include a fluorine atom, a chlorine atom, a methyl group, an ethyl group, an isopropyl group, an isobutyl group, a tert-butyl group, a neopentyl group, a hydroxy group, a hydroxymethyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 2-hydroxy-2-methylpropyl group, a carboxymethyl group, a carbamoylmethyl group, a 2-carboxyethyl group, a 2-carbamoylethyl group, a cyclohexylmethyl group, a cyano group, an acetyl group, a propionyl group, an isobutyryl group, a 2,2-dimethylpropionyl group, a pyrrolidinocarbonyl group, a piperidinocarbonyl group, a 4-hydroxypiperidinocarbonyl group, a 3-hydroxypyrrolidinocarbonyl group, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, an isopropoxycarbonyl group, a tert-butoxycarbonyl group, a carbamoyl group, a methylcarbamoyl group, a dimethylcarbamoyl group, a diethylcarbamoyl group, a methoxy group, an ethoxy group, a propoxy group, a 2-methoxyethoxy group, a 2-hydroxyethoxy group, a carboxymethoxy group, a methoxycarbonylmethoxy group, a carbamoylmethoxy group, a methylcarbamoylmethoxy group, a dimethylcarbamoylmethoxy group, an amino group, a methylamino group, a dimethylamino group, an acetylamino group, an N-methyl-N-acetylamino group, a 2-(methoxymethoxy)ethyl group and the like.

p is an integer of 0, or 1 to 4, preferably, an integer of 0, or 1 to 3.

In type A, specifically preferable examples of R^(b) include a phenyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group, a 2-chlorophenyl group, a 3-chlorophenyl group, a 4-chlorophenyl group, a 3,5-dichlorophenyl group, a 2-methylphenyl group, a 3-methylphenyl group, a 4-methylphenyl group, a 2-(hydroxymethyl)phenyl group, a 4-(hydroxymethyl)phenyl group, a 4-hydroxyphenyl group, a 2-methoxyphenyl group, a 3-methoxycarbonylphenyl group, a 4-methoxyphenyl group, a 3-chloro-4-methoxyphenyl group, a 3-chloro-4-methoxycarbonylphenyl group, a 2-carboxyphenyl group, a 3-carboxyphenyl group, a 4-carboxyphenyl group, a 2-ethoxycarbonylphenyl group, a 4-ethoxycarbonylphenyl group, a 4-(tert-butoxycarbonyl)phenyl group, a 3-carbamoylphenyl group, a 3-(methylcarbamoyl)phenyl group, a 3-(dimethylcarbamoyl)phenyl group, a 2-carbamoylphenyl group, a 2-(methylcarbamoyl)phenyl group, a 2-(dimethylcarbamoyl)phenyl group, a 4-carbamoylphenyl group, a 4-(methylcarbamoyl)phenyl group, a 4-(dimethylcarbamoyl)phenyl group, a 3-chloro-4-carboxyphenyl group, a 3-chloro-4-carbamoylphenyl group, a 3-chloro-4-(methylcarbamoyl)phenyl group, a 3-chloro-4-(dimethylcarbamoyl)phenyl group, a 4-aminophenyl group, a 2-(acetylamino)phenyl group, a 4-(acetylamino)phenyl group, a 3-cyanophenyl group, a 4-cyanophenyl group, a benzyl group, a 2-phenylethenyl group, a benzoyl group, a phenoxy group, a phenylamino group, an N-phenyl-N-methylamino group, a benzyloxy group, a cyclopropyl group, a cyclohexyl group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cyclobutanecarbonyl group, a cyclopentanecarbonyl group, a cyclopropylmethyloxy group, a cyclobutylmethyloxy group, a cyclopentylmethyloxy group, a cyclohexylmethyloxy group, a 2-(adamantan-1-yl)ethoxy group, a 2-(3-hydroxyadamantan-1-yl)ethoxy group, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a 2-thienyl group, a 3-thienyl group, a 2-methyl-4-pyridyl group, a 5-pyrimidinyl group, a 5-oxazolyl group, a 3-methyl-1,2,4-oxadiazol-5-yl group, a 1-methyl-pyrazol-4-yl group, a 1,3,5-trimethyl-pyrazol-4-yl group, a 1-ethyl-pyrazol-4-yl group, a 1-isopropyl-pyrazol-4-yl group, a 1-isobutyl-pyrazol-4-yl group, a 1-tert-butyl-pyrazol-4-yl group, a 1-neopentyl-pyrazol-4-yl group, a 1-carboxymethyl-pyrazol-4-yl group, a 1-(2-hydroxyethyl)-pyrazol-4-yl group, a 1-carbamoylmethyl-pyrazol-4-yl group, a 1-(2-carboxyethyl)-pyrazol-4-yl group, a 1-(2-carbamoylethyl)-pyrazol-4-yl group, a 1-(2-hydroxy-2-methylpropyl)-pyrazol-4-yl group, a 1-cyclohexylmethyl-pyrazol-4-yl group, a pyrazol-1-yl group, a 2-thienylcarbonyl group, a 2-thienylmethyloxy group, a pyrazol-1-ylmethyl group, a 3-(2-oxopyrrolidino)propyl group, a 3-(tetrazol-5-yl)propoxy group, a 2-oxopyrrolidino group, a pyrrolidino group, a piperidino group, a morpholino group, a piperazino group, a 2-methylpyrrolidino group, a 3-methylpyrrolidino group, a 4-carboxypiperidino group, a 4-methylpiperazino group, a 4-acetylpiperazino group, a 4-propionylpiperazino group, a 4-isobutyrylpiperazino group, a 4-(2,2-dimethylpropionyl)piperazino group, a 4-(tert-butoxycarbonyl)piperazino group, a 4-(methoxycarbonyl)piperazino group, a 4-(ethoxycarbonyl)piperazino group, a 4-(isopropoxycarbonyl)piperazino group, an aziridinocarbonyl group, an azetidinocarbonyl group, a piperidinocarbonyl group, a pyrrolidinocarbonyl group, a morpholinocarbonyl group, a 2-methylazetidinocarbonyl group, a 3-methylazetidinocarbonyl group, a 3-hydroxyazetidinocarbonyl group, a 3-hydroxymethylazetidinocarbonyl group, a 3-methoxyazetidinocarbonyl group, a 3-ethoxyazetidinocarbonyl group, a 3-propoxyazetidinocarbonyl group, a 3-(2-methoxyethoxy)azetidinocarbonyl group, a 3-(2-hydroxyethoxy)azetidinocarbonyl group, a 3-(carboxymethoxy)azetidinocarbonyl group, a 3-(methoxycarbonylmethoxy)azetidinocarbonyl group, a 3-(carbamoylmethoxy)azetidinocarbonyl group, a 3-(methylcarbamoylmethoxy)azetidinocarbonyl group, a 3-(dimethylcarbamoylmethoxy)azetidinocarbonyl group, a 2-methoxycarbonylazetidinocarbonyl group, a 2-carboxyazetidinocarbonyl group, a 2-(ethylcarbamoyl)azetidinocarbonyl group, a 2-(propylcarbamoyl)azetidinocarbonyl group, a 3-methoxycarbonylazetidinocarbonyl group, a 3-carboxyazetidinocarbonyl group, a 3-carbamoylazetidinocarbonyl group, a 3-(methylcarbamoyl)azetidinocarbonyl group, a 3-(dimethylcarbamoyl)azetidinocarbonyl group, a 3-dimethylaminoazetidinocarbonyl group, a 3-(diethylcarbamoyl)azetidinocarbonyl group, a 3-(pyrrolidinocarbonyl)azetidinocarbonyl group, a 3-(3-hydroxypyrrolidinocarbonyl)azetidinocarbonyl group, a 3-(piperidinocarbonyl)azetidinocarbonyl group, a 3-(4-hydroxypiperidinocarbonyl)azetidinocarbonyl group, a 2-methylpyrrolidinocarbonyl group, a 3-hydroxypyrrolidinocarbonyl group, a 2-methoxycarbonylpyrrolidinocarbonyl group, a 3-methoxycarbonylpyrrolidinocarbonyl group, a 2-carboxypyrrolidinocarbonyl group, a 3-carboxypyrrolidinocarbonyl group, a 2-carbamoylpyrrolidinocarbonyl group, a 2-(methylcarbamoyl)pyrrolidinocarbonyl group, a 2-(dimethylcarbamoyl)pyrrolidinocarbonyl group, a 3-carbamoylpyrrolidinocarbonyl group, a 3-(methylcarbamoyl)pyrrolidinocarbonyl group, a 3-(dimethylcarbamoyl)pyrrolidinocarbonyl group, a 2-(hydroxymethyl)pyrrolidinocarbonyl group, a 3-(hydroxymethyl)pyrrolidinocarbonyl group, a 3-methylaminopyrrolidinocarbonyl group, a 3-dimethylaminopyrrolidinocarbonyl group, a 3-(N-acetyl-N-methylamino)pyrrolidinocarbonyl group, a 4-hydroxypiperidinocarbonyl group, a 4-methoxycarbonylpiperidinocarbonyl group, a 4-methoxycarbonylpiperidino group, a 4-ethoxycarbonylpiperidinocarbonyl group, a 4-ethoxycarbonylpiperidino group, a 4-carboxypiperidinocarbonyl group, a 4-carbamoylpiperidinocarbonyl group, a 4-carbamoylpiperidino group, a 4-(methylcarbamoyl)piperidinocarbonyl group, a 4-(methylcarbamoyl)piperidino group, a 4-(dimethylcarbamoyl)piperidinocarbonyl group, a 4-(dimethylcarbamoyl)piperidino group, a 4-(hydroxymethyl)piperidinocarbonyl group, a 2-(2-oxopyrrolidino)ethoxy group, a 2-(5-hydroxymethyl-2-oxopyrrolidino)ethoxy group, a 3-(2-oxopyrrolidino)propoxy group, a 2-(2-oxopiperidino)ethoxy group, a 3-(2-oxopiperidino)propoxy group, a 2-(2-oxo-1,3-oxazolidin-3-yl)ethoxy group, a 2-(1,1-dioxoisothiazolidin-2-yl)ethoxy group, a 2-(2-oxo-imidazolidin-1-yl)ethoxy group, a 2-(hexahydro-2-oxo-1,3-oxazin-3-yl)ethoxy group, a 2-(3-oxomorpholino)ethoxy group, a (2-oxopyrrolidin-5-yl)methoxy group, an (1-methyl-2-oxopyrrolidin-5-yl)methoxy group, an (1-(3-hydroxypropyl)-2-oxopyrrolidin-5-yl)methoxy group, an (1-(2-(methoxymethoxy)ethyl)-2-oxopyrrolidin-5-yl)methoxy group, an (1-(2-hydroxyethyl)-2-oxopyrrolidin-5-yl)methoxy group, an azetidinocarbonylmethoxy group, a pyrrolidinocarbonylmethoxy group, a piperidinocarbonylmethoxy group, a morpholinocarbonylmethoxy group, a (3-hydroxyazetidino)carbonylmethoxy group, a (3-hydroxymethylazetidino)carbonylmethoxy group, a (2-hydroxymethylpyrrolidino)carbonylmethoxy group, a (3-hydroxypyrrolidino)carbonylmethoxy group, a (4-hydroxypiperidino)carbonylmethoxy group, a (4-hydroxymethylpiperidino)carbonylmethoxy group and the like.

Specific structural formulas of R^(b) in type A are as follows.

[Type B]

In type B, preferable examples of R^(b) include

(1) a hydrogen atom, (2) a halogen atom (particularly, a fluorine atom, a chlorine atom, a bromine atom), (3) a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, an isopentyl group, a neopentyl group, a 3,3-dimethylbutyl group) optionally substituted by the same or different 1 to 5 substituents selected from group A [particularly, (i) —C(═O)—OR^(A2) wherein R^(A2) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group), (ii) —C(═O)—NR^(A3)R^(A4) wherein R^(A3) and R^(A4) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group, (iii) —OR^(A7) wherein R^(A7) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group), (iv) —NR^(A8)R^(A9) wherein R^(A8) and R^(A9) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group), (v) —NR^(A10)—C(═O)—R^(A11) wherein R^(A10) and R^(A11) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group), and

(vi) —Si—(CH₂—CH₃)₃]

(particularly, a hydroxy group, a methoxy group, a carboxy group, a methoxycarbonyl group, a carbamoyl group, an acetylamino group, a methylamino group, an N-acetyl-N-methylamino group, a triethylsilyl group), (4) a C₂₋₆ alkenyl group (particularly, a 1-propenyl group, a 2-methyl-1-propenyl group), (5) a C₂₋₆ alkynyl group (particularly, an ethynyl group), (6) a cyano group, (7) —C(═O)—R^(b1) wherein R^(b1) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group), (B) —C(═O)—OR^(b2) wherein R^(b2) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group), (9) —C(═O)—NR^(b3)R^(b4) wherein R^(b3) and R^(b4) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group, a propyl group, a butyl group) optionally substituted by the same or different 1 to 5 substituents selected from group B (particularly, a hydroxy group), (10) —OR^(b7) wherein R^(b7) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a hexyl group) optionally substituted by the same or different 1 to 5 substituents selected from group B [particularly, (i) —C(═O)—OR^(B2) wherein R^(B2) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group), (ii) —C(═O)—NR^(B3)R^(B4) wherein R^(B3) and R^(B4) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group) optionally substituted by the same or different 1 to 5 substituents selected from group C (particularly, a hydroxy group, a carboxyl group), (iii) —OR^(B7) wherein R^(B7) is a hydrogen atom or a C₁₋₆ alkyl group, (iv) —NR^(B8)R^(B9) wherein R^(B8) and R^(B9) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group C (particularly, a carboxyl group), (v) —NR^(B10)—C(═O)—R^(B11) wherein R^(B10) and R^(B11) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group) optionally substituted by the same or different 1 to 5 substituents selected from group C (particularly, a hydroxy group, a carboxyl group, a trifluoroacetyl group), (vi) —NR^(B12)—S(═O)₂—R^(B13) wherein R^(B12) and R^(B13) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group), and (vii) —NR^(B14)—C(═O)—OR^(B15) wherein R^(B14) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group, a tert-butyl group), and R^(B15) is a C₁₋₆ alkyl group (particularly, a methyl group, a tert-butyl group)] (particularly, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a hydroxy group, a carbamoyl group, a methylcarbamoyl group, a dimethylcarbamoyl group, an amino group, a methylamino group, a dimethylamino group, a tert-butoxycarbonylamino group, an acetylamino group, an N-tert-butoxycarbonyl-N-methylamino group, an N-acetyl-N-methylamino group, an N-hydroxyacetyl-N-methylamino group, an N-acetyl-N-(2-hydroxyethyl)amino group, an N-(2-hydroxyethyl)carbamoyl group, an N-(2-hydroxyethyl)-N-methylcarbamoyl group, an N,N-bis(2-hydroxyethyl)carbamoyl group, an N-methyl-N-methanesulfonylamino group, an N-acetyl-N-(2-carboxyethyl)amino group, an N-carboxymethyl-N-methylamino group, an N-carboxymethyl-N-methylcarbamoyl group, an N-(2-carboxyethyl)-N-methylcarbamoyl group, a 3-(trifluoroacetyl)propionylamino group, an N-(2,2-dimethylpropionyl)-N-methylamino group, an N-(2,2-dimethyl-3-hydroxypropionyl)-N-methylamino group, an N-(2-hydroxy-2-methylpropionyl)-N-methylamino group), (11) —NR^(b8)R^(b9) wherein R^(b8) and R^(b9) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group), (12) —NR^(b10)—C(═O)—R^(b11) wherein R^(b10) and R^(b11) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group), or (13) —O—C(═O)—NR^(b14)R^(b15) wherein R^(b14) and R^(b15) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group).

In type B, specifically preferable examples of R^(b) include, a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a neopentyl group, a 3,3-dimethylbutyl group, a hydroxymethyl group, a methoxymethyl group, a 2-hydroxyethyl group, a 2-hydroxy-2-methylpropyl group, a 3-hydroxy-3-methylbutyl group, a 4-hydroxy-3,3-dimethylbutyl group, a methoxycarbonylmethyl group, a carboxymethyl group, a carbamoylmethyl group, an acetylaminomethyl group, a methylaminomethyl group, an N-acetyl-N-methylaminomethyl group, a (triethylsilyl)ethyl group, a 1-propenyl group, a 2-methyl-1-propenyl group, an ethynyl group, an acetyl group, a carboxyl group, a methoxycarbonyl group, a carbamoyl group, a methylcarbamoyl group, an ethylcarbamoyl group, a propylcarbamoyl group, a dimethylcarbamoyl group, a diethylcarbamoyl group, an N-methyl-N-ethylcarbamoyl group, an N-(2-hydroxyethyl)carbamoyl group, an N-(2-hydroxyethyl)-N-methylcarbamoyl group, an N-methyl-N-propylcarbamoyl group, an N-(3-hydroxypropyl)carbamoyl group, an N-(3-hydroxypropyl)-N-methylcarbamoyl group, an N-butyl-N-methylcarbamoyl group, an N-(4-hydroxybutyl) carbamoyl group, an N-(4-hydroxybutyl)-N-methylcarbamoyl group, a hydroxy group, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a pentoxy group, an isopentoxy group, a neopentoxy group, a hexyloxy group, a carboxymethoxy group, a methoxycarbonylmethoxy group, a carbamoylmethoxy group, a methylcarbamoylmethoxy group, a dimethylcarbamoylmethoxy group, a (2-hydroxyethyl)carbamoylmethoxy group, a bis(2-hydroxyethyl)carbamoylmethoxy group, an N-(2-hydroxyethyl)-N-methylcarbamoylmethoxy group, an N-carboxymethyl-N-methylcarbamoylmethoxy group, a 2-hydroxyethoxy group, a 2-carboxyethoxy group, a 2-hydroxy-1,1-dimethylethoxy group, a 2-carbamoylethoxy group, a 1-carbamoylethoxy group, a 2-(methylcarbamoyl)ethoxy group, a 2-(dimethylcarbamoyl)ethoxy group, a 2-aminoethoxy group, a 2-(methylamino)ethoxy group, a 2-(dimethylamino)ethoxy group, a 2-(tert-butoxycarbonylamino)ethoxy group, a 2-(N-tert-butoxycarbonyl-N-methylamino)ethoxy group, a 2-(acetylamino)ethoxy group, a 2-(N-acetyl-N-methylamino) ethoxy group, a 2-(N-hydroxyacetyl-N-methylamino)ethoxy group, a 2-(N-acetyl-N-(2-hydroxyethyl)amino)ethoxy group, a 2-(N-acetyl-N-methylamino)-1-methylethoxy group, a 2-(N-acetyl-N-methylamino)-2-methylethoxy group, a 2-(N-methanesulfonyl-N-methylamino)-2-methylethoxy group, a 2-(N-methanesulfonyl-N-methylamino)ethoxy group, a 2-(N-acetyl-N-(2-carboxyethyl)amino)ethoxy group, a 2-(N-carboxymethyl-N-methylamino)ethoxy group, a 2-(4-oxo-5,5,5-trifluoropentanoylamino)ethoxy group, a 2-(N-(2,2-dimethylpropionyl)-N-methylamino)ethoxy group, a 2-(N-(2,2-dimethyl-3-hydroxypropionyl)-N-methylamino)ethoxy group, a 2-(N-(2-methyl-2-hydroxypropionyl)-N-methylamino)ethoxy group, a 2-hydroxy-1-(hydroxymethyl)ethoxy group, a 3-hydroxypropoxy group, a 3-ethoxycarbonylpropoxy group, a 3-carboxypropoxy group, a 3-carbamoylpropoxy group, a 3-(methylcarbamoyl)propoxy group, a 3-(dimethylcarbamoyl)propoxy group, a 3-aminopropoxy group, a 3-(methylamino)propoxy group, a 3-(dimethylamino)propoxy group, a 3-(acetylamino)propoxy group, a 3-(N-acetyl-N-methylamino)propoxy group, a 3-(N-acetyl-N-methylamino)-2-hydroxypropoxy group, a 2-(N-acetyl-N-methylamino)propoxy group, a 2,3-dihydroxypropoxy group, a 2-(hydroxymethyl)-3-hydroxypropoxy group, a 2-hydroxy-2-methylpropoxy group, a 3-hydroxy-2,2-dimethylpropoxy group, a 4-hydroxybutoxy group, a 4-ethoxycarbonylbutoxy group, a 3-carboxybutoxy group, a 4-carboxybutoxy group, a 4-carbamoylbutoxy group, a 4-(methylcarbamoyl)butoxy group, a 4-(dimethylcarbamoyl)butoxy group, a 5-hydroxypentoxy group, a 5-carboxypentoxy group, a 6-hydroxyhexyloxy group, an amino group, a dimethylamino group, a methylamino group, an acetylamino group, an N-acetyl-N-methylamino group, a dimethylaminocarbonyloxy group and the like.

R^(c)

R^(c) is

(1) a hydrogen atom, (2) a halogen atom, (3) a C₁₋₆ alkyl group, (4) —C(═O)—OR^(c1) wherein R^(c1) is a hydrogen atom or a C₁₋₆ alkyl group, (5) —OR^(c2) wherein R^(c2) is a hydrogen atom or a C₁₋₆ alkyl group, (6) —NR^(c3)R^(c4) wherein R^(c3) and R^(c4) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group, or (7) —NR^(c5)—C(═O)—R^(c6) wherein R^(c5) and R^(c6) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group.

As R^(c), preferred is

(1) a hydrogen atom, (2) a halogen atom (particularly, a fluorine atom, a chlorine atom), (3) a methyl group, (4) —C(═O)—OR^(c1) wherein R^(c1) is a hydrogen atom or a methyl group, (5) —OR^(c2) wherein R^(c2) is a hydrogen atom, a methyl group or an ethyl group,

(6) —NH₂, or

(7) —NR^(c5)—C(═O)—R^(c6) wherein R^(c5) and R^(c6) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group, an isopropyl group), particularly preferably, a hydrogen atom.

Specifically preferable examples of R^(c) include a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, a hydroxy group, a methoxy group, an ethoxy group, an amino group, an acetylamino group, a propionylamino group, an isobutyrylamino group, a carboxyl group, a methoxycarbonyl group and the like.

X^(d)

Preferable embodiments of X^(d) are classified into the following type C to type E.

[Type C]

A type wherein X^(d) is C—R^(d), and R^(d) is a group represented by the following formula:

wherein each symbol is as defined above. In this case, compound [I] is represented by the formula [II]

[Type D]

A type wherein X^(d) is C—R^(d), and R^(d) is

(i) a hydrogen atom, (ii) a halogen atom, (iii) a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group A, (iv) a C₂₋₆ alkenyl group optionally substituted by the same or different 1 to 5 substituents selected from group C, (v) a C₂₋₆ alkynyl group optionally substituted by the same or different 1 to 5 substituents selected from group C, (vi) a cyano group, (vii) —C(═O)—R^(d1) wherein R^(d1) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (viii) —C(═O)—OR^(d2) wherein R^(d2) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (ix) —C(═O)—NR^(d3)R^(d4) wherein R^(d3) and R^(d4) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (x) —C(═O)—NR^(d5)—OR^(d6) wherein R^(d5) and R^(d6) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (xi) —OR^(d7) wherein R^(d7) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (xii) —NR^(d8)R^(d9) wherein R^(d8) and R^(d9) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (xiii) —NR^(d10)—C(═O)—R^(d11) wherein R^(d10) and R^(d11) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, or (xiv) —NR^(d12)—C(═O)—OR^(d13) wherein R^(d12) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, and R^(d13) is a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B.

[Type E]

In this type, X^(d) is a nitrogen atom.

In this case, compound [I] is represented by the formula [V]

Preferable embodiment of type C is explained in the following.

[Type C]

As Y^(d), preferred is

(I) a single bond, or. (II) —C(═O)—, more preferred is a single bond.

As ring U, preferred is

(I) a C₆₋₁₀ aryl group, (II) a C₃₋₁₀ cycloalkyl group, (III) a monocyclic aromatic heterocyclic group which contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms, or (IV) a monocyclic non-aromatic heterocyclic group which contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms, more preferred is (I) a phenyl group, (II) a cyclopropyl group, (III) a monocyclic aromatic heterocyclic group selected from an oxazolyl group, a pyridyl group, a 1,3,4-oxadiazolyl group, a 1,2,4-oxadiazolyl group, a tetrazolyl group, a pyrazolyl group, a pyrimidinyl group, a thienyl group, a 1,2,4-triazolyl group, or (IV) an aziridinyl group.

R^(k) is preferably

(1) a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E, (2) a C₁₋₆ alkyl group substituted by a C₆₋₁₀ aryl group optionally substituted by the same or different 1 to 5 substituents selected from group F, (3) a C₁₋₆ alkyl group substituted by a C₃₋₁₀ cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (4) a C₁₋₆ alkyl group substituted by a C₅₋₁₀ bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (5) a C₁₋₆ alkyl group substituted by a monocyclic aromatic heterocyclic group optionally substituted by the same or different 1 to 5 C₁₋₆ alkyl groups (the monocyclic aromatic heterocyclic group contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms), (6) a C₃₋₁₀ cycloalkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F, or (7) a C₅₋₁₀ bridged cycloalkyl group optionally substituted by the same or different 1 to 5 substituents selected from group F, more preferably, (1) a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a neopentyl group, a 1,1-dimethylpropyl group, a 1-ethylpropyl group, a 1,1,2-trimethylpropyl group) optionally substituted by the same or different 1 to 5 substituents selected from group E (particularly, a halogen atom (particularly, a fluorine atom), a hydroxy group, a carboxyl group, a carbamoyl group, a methylcarbamoyl group, an ethylcarbamoyl group, an isopropylcarbamoyl group, a dimethylcarbamoyl group, an acetylamino group, an N-acetyl-N-methylamino group, a methanesulfonylamino group, a cyano group), (2) a C₁₋₆ alkyl group substituted by a C₆₋₁₀ aryl group (particularly, a benzyl group), (3) a C₁₋₆ alkyl group substituted by a C₃₋₁₀ cycloalkyl (particularly, a cyclohexylmethyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F (particularly, a hydroxy group), (4) a C₁₋₆ alkyl group substituted by a C₅₋₁₀ bridged cycloalkyl (particularly, an adamantan-1-ylmethyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F (particularly, a hydroxy group), (5) a C₁₋₆ alkyl group (particularly, a propyl group) substituted by a monocyclic aromatic heterocyclic group which contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms (particularly, tetrazolyl) (particularly, a 3-(5-tetrazolyl)propyl group) optionally substituted by the same or different 1 to 5 C₁₋₆ alkyl groups (particularly, a methyl group), (6) a C₃₋₁₀ cycloalkyl group, (particularly, a cyclohexyl group, a cyclopentyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F (particularly, a hydroxymethyl group, a carboxyl group), (7) a C₅₋₁₀ bridged cycloalkyl group (particularly, a 1-adamantyl group).

Specifically preferable examples of R^(k) include

a methyl group, an ethyl group, an isopropyl group, an isobutyl group, a tert-butyl group, a neopentyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 2,3-dihydroxypropyl group, a 2-hydroxy-1-(hydroxymethyl)ethyl group, a carboxymethyl group, a carbamoylmethyl group, a methylcarbamoylmethyl group, an ethylcarbamoylmethyl group, an isopropylcarbamoylmethyl group, a dimethylcarbamoylmethyl group, a 2-carboxyethyl group, a 2-carbamoylethyl group, a 2-(methylcarbamoyl)ethyl group, a 2-(dimethylcarbamoyl)ethyl group, a 2-(acetylamino)ethyl group, a 2-(N-acetyl-N-methylamino)ethyl group, a 2-hydroxy-1,1-dimethylethyl group, a 2-hydroxy-1-(hydroxymethyl)-1-methylethyl group, a 1-carbamoyl-1-methylethyl group, a 1-methylcarbamoyl-1-methylethyl group, a 1-dimethylcarbamoyl-1-methylethyl group, a 2-hydroxy-1,1-bis(hydroxymethyl)ethyl group, a 3-hydroxy-2-(hydroxymethyl)propyl group, a 2-hydroxy-2-methylpropyl group, a 2-hydroxy-1,1,2-trimethylpropyl group, a 2-hydroxy-3,3,3-trifluoropropyl group, a 3-methanesulfonylaminopropyl group, a 3-(5-tetrazolyl)propyl group, a 3-(1-methyl-5-tetrazolyl)propyl group, a 3-(2-methyl-5-tetrazolyl)propyl group, a 1,1-bis(hydroxymethyl)propyl group, a 3-hydroxy-1-(2-hydroxyethyl)propyl group, a 3-carboxypropyl group, a 4-carboxybutyl group, a 1-carboxy-1-methylethyl group, a 2-carboxy-2-methylpropyl group, a 2-carboxy-1,1-dimethylethyl group, a cyanomethyl group, a benzyl group, an (1-hydroxycyclohexyl)methyl group, a 3-hydroxyadamantan-1-ylmethyl group, a 1-hydroxymethylcyclohexyl group, a 1-hydroxymethylcyclopentyl group, a 1-carboxycyclopentyl group, a 1-adamantyl group and the like.

m is an integer of 0, or 1 to 4, preferably, an integer of 0, or 1 to 3.

Specifically preferable examples of R^(d) include a phenyl group, a cyclopropyl group, a cyclopropanecarbonyl group, an oxazol-5-yl group, a 2-methyl-oxazol-5-yl group, an oxazol-2-yl group, a 2-(2-hydroxy-1-(hydroxymethyl)ethyl)-oxazol-5-yl group, a 2-pyridyl group, a 3-pyridyl group, a 4-methyl-3-pyridyl group, a 6-methyl-3-pyridyl group, a 4-pyridyl group, a 1,3,4-oxadiazol-2-yl group, a 5-methyl-1,3,4-oxadiazol-2-yl group, a 3-methyl-1,2,4-oxadiazol-5-yl group, a 5-methyl-1,2,4-oxadiazol-3-yl group, a 3-(2-hydroxy-1-(hydroxymethyl)ethyl)-1,2,4-oxadiazol-5-yl group, a 2-methyl-5-tetrazolyl group, a 1-methyl-5-tetrazolyl group, a pyrazol-4-yl group, a 1-methyl-pyrazol-4-yl group, a 1,3,5-trimethyl-pyrazol-4-yl group, a 1-ethyl-pyrazol-4-yl group, a 1-isopropyl-pyrazol-4-yl group, a 1-isobutyl-pyrazol-4-yl group, a 1-tert-butyl-pyrazol-4-yl group, a 1-neopentyl-pyrazol-4-yl group, a 1-benzyl-pyrazol-4-yl group, a 1-(adamantan-1-yl)-pyrazol-4-yl group, a 1-(2-hydroxyethyl)-pyrazol-4-yl group, a 1-(3-hydroxypropyl)-pyrazol-4-yl group, a 1-(2-(acetylamino)ethyl)-pyrazol-4-yl group, a 1-(2-(N-acetyl-N-methylamino)ethyl)-pyrazol-4-yl group, a 1-carboxymethyl-pyrazol-4-yl group, a 1-carbamoylmethyl-pyrazol-4-yl group, a 1-methylcarbamoylmethyl-pyrazol-4-yl group, a 1-dimethylcarbamoylmethyl-pyrazol-4-yl group, a 1-ethylcarbamoylmethyl-pyrazol-4-yl group, a 1-isopropylcarbamoylmethyl-pyrazol-4-yl group, a 1-(2-carboxyethyl)-pyrazol-4-yl group, a 1-(2-carbamoylethyl)-pyrazol-4-yl group, a 1-(2-(methylcarbamoyl)ethyl)-pyrazol-4-yl group, a 1-(2-(dimethylcarbamoyl)ethyl)-pyrazol-4-yl group, a 1-(3-carboxypropyl)-pyrazol-4-yl group, a 1-(4-carboxybutyl)-pyrazol-4-yl group, a 5-pyrimidinyl group, a 3-thienyl group, a 3-methyl-1,2,4-triazol-5-yltriazolyl group, a 3-methyl-1,2,4-triazol-5-yl group, a 1-(1-hydroxycyclohexylmethyl)-pyrazol-4-yl group, a 1-(1-(hydroxymethyl)cyclohexyl)-pyrazol-4-yl group, a 1-(1-(hydroxymethyl)cyclopentyl)-pyrazol-4-yl group, a 1-(1-(3-hydroxyadamantan-1-ylmethyl)-pyrazol-4-yl group, a 1-(1-carboxycyclohexyl)-pyrazol-4-yl group, a 1-(1-carboxycyclopentyl)-pyrazol-4-yl group, a 1-(2,3-dihydroxypropyl)-pyrazol-4-yl group, a 1-(1-carboxy-1-methylethyl)-pyrazol-4-yl group, a 1-(2-carboxy-2-methylpropyl)-pyrazol-4-yl group, a 1-(2-carboxy-1,1-dimethylethyl)-pyrazol-4-yl group, a 1-(2-hydroxy-1,1-dimethylethyl)-pyrazol-4-yl group, a 1-(2-hydroxy-1-(hydroxymethyl)ethyl)-pyrazol-4-yl group, a 1-(2-hydroxy-1-(hydroxymethyl)-1-methylethyl)-pyrazol-4-yl group, a 1-(1-carbamoyl-1-methylethyl)-pyrazol-4-yl group, a 1-(1-methylcarbamoyl-1-methylethyl)-pyrazol-4-yl group, a 1-(1-dimethylcarbamoyl-1-methylethyl)-pyrazol-4-yl group, a 1-(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)-pyrazol-4-yl group, a 1-(3-hydroxy-2-(hydroxymethyl)propyl)-pyrazol-4-yl group, a 1-(2-hydroxy-2-methylpropyl)-pyrazol-4-yl group, a 1-(2-hydroxy-1,1,2-trimethylpropyl)-pyrazol-4-yl group, a 1-(2-hydroxy-3,3,3-trifluoropropyl)-pyrazol-4-yl group, a 1-(3-methanesulfonylaminopropyl)-pyrazol-4-yl group, a 1-(3-(5-tetrazolyl)propyl)-pyrazol-4-yl group, a 1-(3-(1-methyl-5-tetrazolyl)propyl)-pyrazol-4-yl group, a 1-(3-(2-methyl-5-tetrazolyl)propyl)-pyrazol-4-yl group, a 1-(1,1-bis(hydroxymethyl)propyl)-pyrazol-4-yl group, a 1-(3-hydroxy-1-(2-hydroxyethyl)propyl)-pyrazol-4-yl group, an aziridinocarbonyl group and the like.

Ring U is preferably a monocyclic aromatic heterocyclic group.

Furthermore, a compound wherein Y^(d) is a single bond is preferable, and

more preferred is a pyrazolyl group (particularly, a pyrazol-4-yl group) or a pyrimidinyl group (particularly, a pyrimidin-5-yl group) for ring U. Still more preferred is a compound represented by the following formula, which is a compound wherein ring U is a pyrazol-4-yl group:

wherein

R^(m) is

(1) a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E, (2) a C₁₋₆ alkyl group substituted by a C₆₋₁₀ aryl group optionally substituted by the same or different 1 to 5 substituents selected from group F, (3) a C₁₋₆ alkyl group substituted by a C₃₋₁₀ cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (4) a C₁₋₆ alkyl group substituted by a C₆₋₁₀ bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (5) a C₁₋₆ alkyl group substituted by a monocyclic aromatic heterocyclic group optionally substituted by the same or different 1 to 5 C₁₋₆ alkyl groups (the monocyclic aromatic heterocyclic group contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms), (6) a C₃₋₁₀ cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, or (7) a C₅₋₁₀ bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, and other symbols are as defined above.

Here, as R^(m), preferred is

(1) a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a neopentyl group, a 1,1-dimethylpropyl group, a 1-ethylpropyl group, a 1,1,2-trimethylpropyl group) optionally substituted by the same or different 1 to 5 substituents selected from (i) a halogen atom (particularly, a fluorine atom), (ii) —C(═O)—OR^(E2) wherein R^(E2) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F, (iii) —C(═O)—NR^(E3)R^(E4) wherein R^(E3) and R^(E4) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group, an isopropyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F, (iv) —OR^(E7) wherein R^(E7) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F, (v) —NR^(E12)—C(═O)—R^(E13) wherein R^(E12) and R^(E13) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F, and (vi) —NR^(E16)—S(═O)₂—R^(E17) wherein R^(E16) and R^(E17) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group), (2) a C₁₋₆ alkyl group substituted by a C₆₋₁₀ aryl group (particularly, a benzyl group), (3) a C₁₋₆ alkyl group substituted by a C₃₋₁₀ cycloalkyl (particularly, a cyclohexylmethyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F (particularly, a hydroxy group), (4) a C₁₋₆ alkyl group substituted by a C₅₋₁₀ bridged cycloalkyl (particularly, an adamantan-1-ylmethyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F (particularly, a hydroxy group), (5) a C₁₋₆ alkyl group (particularly, a propyl group) substituted by a monocyclic aromatic heterocyclic group which contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms (particularly, tetrazolyl) (particularly, a 3-(5-tetrazolyl)propyl group) optionally substituted by the same or different 1 to 5 C₁₋₆ alkyl groups (particularly, a methyl group), (6) a C₃₋₁₀ cycloalkyl group (particularly, a cyclohexyl group, a cyclopentyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F (particularly, a hydroxy group, a hydroxymethyl group, a carboxyl group), and (7) a C₅₋₁₀ bridged cycloalkyl group (particularly, an adamantyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F.

Specifically preferable examples of R^(m) include a methyl group, an ethyl group, an isopropyl group, an isobutyl group, a tert-butyl group, a neopentyl group, a 1-benzyl group, an adamantan-1-yl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 2-(acetylamino)ethyl group, a 2-(N-acetyl-N-methylamino)ethyl group, a carboxymethyl group, a carbamoylmethyl group, a methylcarbamoylmethyl group, a dimethylcarbamoylmethyl group, an ethylcarbamoylmethyl group, an isopropylcarbamoylmethyl group, a 2-carboxyethyl group, a 2-carbamoylethyl group, a 2-(methylcarbamoyl)ethyl group, a 2-(dimethylcarbamoyl)ethyl group, a 3-carboxypropyl group, a 4-carboxybutyl group, a 1-hydroxycyclohexylmethyl group, a 1-(hydroxymethyl)cyclohexyl group, a 1-(hydroxymethyl)cyclopentyl group, a (3-hydroxyadamantan-1-yl)methyl group, a 1-carboxycyclohexyl group, a 1-carboxycyclopentyl group, a 2,3-dihydroxypropyl group, a 1-carboxy-1-methylethyl group, a 2-carboxy-2-methylpropyl group, a 2-carboxy-1,1-dimethylethyl group, a 2-hydroxy-1-(hydroxymethyl)ethyl group, a 3-hydroxy-2-(hydroxymethyl)propyl group, a 2-hydroxy-1,1-dimethylethyl group, a 2-hydroxy-1-(hydroxymethyl)-1-methylethyl group, a 1-carbamoyl-1-methylethyl group, a 1-methylcarbamoyl-1-methylethyl group, a 1-dimethylcarbamoyl-1-methylethyl group, a 2-hydroxy-1,1-bis(hydroxymethyl)ethyl group, a 2-hydroxy-2-methylpropyl group, a 2-hydroxy-1,1,2-trimethylpropyl group, a 2-hydroxy-3,3,3-trifluoropropyl group, a 3-methanesulfonylaminopropyl group, a 3-(5-tetrazolyl)propyl group, a 3-(1-methyl-5-tetrazolyl)propyl group, a 3-(2-methyl-5-tetrazolyl)propyl group, a 1,1-bis(hydroxymethyl)propyl group, a 3-hydroxy-1-(2-hydroxyethyl)propyl group and the like.

In other embodiments, as R^(m), preferred is

(1) a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E′, (2) a C₁₋₆ alkyl group substituted by a C₃₋₁₀ cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (3) a C₁₋₆ alkyl group substituted by a C₅₋₁₀ bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (4) a C₃₋₁₀ cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, or (5) a C₅₋₁₀ bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, more preferred is, (1) a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a neopentyl group) optionally substituted by the same or different 1 to 5 substituents selected from (i) —C(═O)—OR^(E2) wherein R^(E2) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F, (ii) —C(═O)—NR^(E3)R^(E4) wherein R^(E3) and R^(E4) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group, an isopropyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F, (iii) —OR^(E7) wherein R^(E7) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F, and (iv) —NR^(E12)—C(═O)—R^(E13) wherein R^(E12) and R^(E13) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F, (2) a C₃₋₁₀ cycloalkyl group (particularly, a cyclohexyl group, a cyclopentyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F (particularly, a hydroxy group, a hydroxymethyl group, a carboxyl group), or (3) a C₅₋₁₀ bridged cycloalkyl group (particularly, an adamantyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F, and further preferably, (1) a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a neopentyl group) optionally substituted by the same or different 1 to 5 substituents selected from (i) —C(═O)—OR^(E2) wherein R^(E2) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F, and (ii) —OR^(E7) wherein R^(E7) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F, (2) a C₃₋₁₀ cycloalkyl group (particularly, a cyclohexyl group, a cyclopentyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F (particularly, a hydroxy group, a hydroxymethyl group, a carboxyl group), or (3) a C₅₋₁₀ bridged cycloalkyl group (particularly, a 1-adamantyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F.

In the above-mentioned formula [III],

R^(c) is preferably a hydrogen atom; R^(b) is preferably (1) a hydrogen atom, (2) a halogen atom, (3) a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group A, (4) a C₂₋₆ alkenyl group optionally substituted by the same or different 1 to 5 substituents selected from group C, (5) a C₂₋₆ alkynyl group optionally substituted by the same or different 1 to 5 substituents selected from group C, (6) a cyano group, (7) —C(═O)—R^(b1) wherein R^(b1) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (8) —C(═O)—OR^(b2) wherein R^(b2) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (9) —C(═O)—NR^(b3)R^(b4) wherein R^(b3) and R^(b4) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (10) —C(═O)—NR^(b5)—OR^(b6) wherein R^(b5) and R^(b6) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (11) —OR^(b7) wherein R^(b7) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (12) —NR^(b8)R^(b9) wherein R^(b8) and R^(b9) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (13) —NR^(b10)—C(═O)—R^(b11) wherein R^(b10) and R^(b11) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (14) —NR^(b12)—C(═O)—OR^(b13) wherein R^(b12) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, and R^(b13) is a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, or (15) —O—C(═O)—NR^(b14)R^(b15) wherein R^(b14) and R^(b15) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B; R^(a) is preferably a hydrogen atom; and n is preferably 0.

In addition, a compound wherein Y^(d) is a single bond and ring U is a pyrimidin-5-yl group, which is represented by the following formula:

wherein each symbol is as defined above, is preferable.

Here, m is preferably 0;

R^(a) is preferably a hydrogen atom; and n is preferably 0.

In the following, a preferable embodiment of type D is explained.

[Type D]

R^(d) is preferably

(i) a hydrogen atom, (ii) a halogen atom (particularly, a fluorine atom, a chlorine atom, a bromine atom), (iii) a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group A [particularly, (1) a halogen atom (particularly, a fluorine atom), (2) a cyano group, (3) —C(═O)—NR^(A3)R^(A4) wherein R^(A3) and R^(A4) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group, (4) —OR^(A7) wherein R^(A7) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group), and (5) —NR^(A8)R^(A9) wherein R^(A8) and R^(A9) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group)] (particularly, a fluorine atom, a hydroxy group, a methoxy group, an amino group, a cyano group, a carbamoyl group) (particularly, a methyl group, an ethyl group, an isopropyl group, a trifluoromethyl group, an aminomethyl group), (iv) a C₂₋₆ alkenyl group (particularly, a 1-methylvinyl group), (v) a C₂₋₆ alkynyl group (particularly, an ethynyl group, a 3-hydroxy-1-propynyl group) optionally substituted by the same or different 1 to 5 substituents selected from group C (particularly, a hydroxy group), (vi) a cyano group, (vii) —C(═O)—R^(d1) wherein R^(d1) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group, an isopropyl group), (viii) —C(═O)—OR^(d2) wherein R^(d2) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group, a propyl group, an isopropyl group), (ix) —C(═O)—NR^(d3)R^(d4) wherein R^(d3) and R^(d4) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group), (x) —C(═O)—NR^(d5)—OR^(d6) wherein R^(d5) and R^(d6) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group), (xi) —OR^(d7) wherein R^(d7) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group), (xii) —NR^(d8)R^(d9) wherein R^(d8) and R^(d9) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group), (xiii) —NR^(d10)—C(═O)—R^(d11) wherein R^(d10) and R^(d11) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group), or (xiv) —NR^(d12)—C(═O)—OR^(d13) wherein R^(d12) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group), and R^(d13) is a C₁₋₆ alkyl group (particularly, a methyl group).

In type D, specifically preferable examples of R^(d) include a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, an ethyl group, a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 1-hydroxy-1-methylethyl group, a methoxymethyl group, a trifluoromethyl group, an aminomethyl group, a cyanomethyl group, a carboxymethyl group, a carbamoylmethyl group, a 1-methylvinyl group, an ethynyl group, a 3-hydroxypropynyl group, a cyano group, an acetyl group, a propionyl group, an isobutyryl group, a carboxy group, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a carbamoyl group, a methylcarbamoyl group, a dimethylcarbamoyl group, an N-methyl-N-methoxycarbamoyl group, a hydroxy group, a methoxy group, an ethoxy group, an amino group, a methylamino group, a dimethylamino group, an acetylamino group, a methoxycarbonylamino group and the like.

As X^(d), type C and type D are preferable, and type C is more preferable.

R^(e)

R^(e) is preferably the same or different and each is

(1) a halogen atom (particularly, a chlorine atom, a fluorine atom), or (2) a C₁₋₆ alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents (particularly, a hydroxy group) selected from group C; more preferably, a fluorine atom, a chlorine atom, a methyl group, a hydroxymethyl group and the like. n

n is an integer of 0, or 1 to 3, preferably an integer of 0, or 1 to 2, particularly preferably 0.

As preferable embodiment of the compound represented by the formula [I], a compound represented by the following formula can be mentioned.

Here, as the compound represented by the formula [I], preferred is a compound represented by the formula [II], more preferred is a compound represented by the formula [III] or a compound represented by the formula [VI].

As a compound represented by the formula [III], preferred is the formula [III-E], and as a compound represented by the formula [VI], preferred is a compound represented by the formula [VI-A].

As a compound represented by the formula [IV], preferred is a compound represented by the formula [IV-D] or [IV-F].

As a compound represented by the formula [IV-D], preferred is a compound wherein R^(a) is a hydrogen atom, R^(c) is a hydrogen atom, R^(d) is —CH₃, —CH₂—OH or —C(═O)—NH₂, and n=0.

As a compound represented by the formula [IV-F], preferred is a compound wherein R^(a) is a hydrogen atom, R^(c) is a hydrogen atom, R^(d) is —CH₃, and n=0.

One example of preferable combination of each symbol in a compound represented by the formula [III] is explained in the following.

In a preferable combination,

R^(a) is a hydrogen atom, a fluorine atom or a chlorine atom, particularly a hydrogen atom,

R^(b) is

(1) a hydrogen atom, (2) a halogen atom, (3) a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group A, (4) a C₂₋₆ alkenyl group optionally substituted by the same or different 1 to 5 substituents selected from group C, (5) a C₂₋₆ alkynyl group optionally substituted by the same or different 1 to 5 substituents selected from group C, (6) a cyano group, (7) —C(═O)—R^(b1) wherein R^(b1) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (8) —C(═O)—OR^(b2) wherein R^(b2) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (9) —C(═O)—NR^(b3)R^(b4) wherein R^(b3) and R^(b4) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents so selected from group B, (10) —C(═O)—NR^(b5)—OR^(b6) wherein R^(b5) and R^(b6) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (11) —OR^(b7) wherein R^(b7) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (12) —NR^(b8)R^(b9) wherein R^(b8) and R^(b9) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (13) —NR^(b10)—C(═O)—R^(b11) wherein R^(b10) and R^(b11) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, (14) —NR^(b12)—C(═O)—OR^(b13) wherein R^(b12) is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, and R^(b13) is a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, or (15) —O—C(═O)—NR^(b14)R^(b15) wherein R^(b14) and R^(b15) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group B, particularly, (1) a hydrogen atom, (2) a halogen atom (particularly, a fluorine atom, a chlorine atom, a bromine atom), (3) a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, an isopentyl group, a neopentyl group, a 3,3-dimethylbutyl group) optionally substituted by the same or different 1 to 5 substituents selected from group A [particularly, (i) —C(═O)—OR^(A2) wherein R^(A2) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group), (ii) —C(═O)—NR^(A3)R^(A4) wherein R^(A3) and R^(A4) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group, (iii) —OR^(A7) wherein R^(A7) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group), (iv) —NR^(A8)R^(A9) wherein R^(A8) and R^(A9) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group), (v) —NR^(A10)—C(═O)—R^(A11) wherein R^(A10) and R^(A11) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group), and

(vi) —Si—(CH₂—CH₃)₃]

(particularly, a hydroxy group, a methoxy group, a carboxy group, a methoxycarbonyl group, a carbamoyl group, an acetylamino group, a methylamino group, an N-acetyl-N-methylamino group, a triethylsilyl group), (4) a C₂₋₆ alkenyl group (particularly, a 1-propenyl group, a 2-methyl-1-propenyl group), (5) a C₂₋₆ alkynyl group (particularly, an ethynyl group), (6) a cyano group, (7) —C(═O)—R^(b1) wherein R^(b1) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group), (8) —C(═O)—OR^(b2) wherein R^(b2) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group), (9) —C(═O)—NR^(b3)R^(b4) wherein R^(b3) and R^(b4) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group, a propyl group, a butyl group) optionally substituted by the same or different 1 to 5 substituents selected from group B (particularly, a hydroxy group), (10) —OR^(b7) wherein R^(b7) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a hexyl group) optionally substituted by the same or different 1 to 5 substituents selected from group B [particularly, (i) —C(═O)—OR^(B2) wherein R^(B2) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group), (ii) —C(═O)—NR^(B3)R^(B4) wherein R^(B3) and R^(B4) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group) optionally substituted by the same or different 1 to 5 substituents selected from group C (particularly, a hydroxy group, a carboxyl group), (iii) —OR^(B7) wherein R^(B7) is a hydrogen atom or a C₁₋₆ alkyl group, (iv) —NR^(B8)R^(B9) wherein R^(B8) and R^(B9) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group C (particularly, a carboxyl group), (v) —NR^(B10)—C(═O)—R^(B11) wherein R^(B10) and R^(B11) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group) optionally substituted by the same or different 1 to 5 substituents selected from group C (particularly, a hydroxy group, a carboxyl group, a trifluoroacetyl group), (vi) —NR^(B12)—S(═O)₂—R^(B13) wherein R^(B12) and R^(B13) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group), and (vii) —NR^(B14)—C(═O)—OR^(B15) wherein R^(B14) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group, a tert-butyl group), and R^(B15) is a C₁₋₆ alkyl group (particularly, a methyl group, a tert-butyl group)] (particularly, a carboxyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a hydroxy group, a carbamoyl group, a methylcarbamoyl group, a dimethylcarbamoyl group, an amino group, a methylamino group, a dimethylamino group, a tert-butoxycarbonylamino group, an acetylamino group, an N-tert-butoxycarbonyl-N-methylamino group, an N-acetyl-N-methylamino group, an N-hydroxyacetyl-N-methylamino group, an N-acetyl-N-(2-hydroxyethyl)amino group, an N-(2-hydroxyethyl)carbamoyl group, an N-(2-hydroxyethyl)-N-methylcarbamoyl group, an N,N-bis(2-hydroxyethyl) carbamoyl group, an N-methyl-N-methanesulfonylamino group, an N-acetyl-N-(2-carboxyethyl)amino group, an N-carboxymethyl-N-methylamino group, an N-carboxymethyl-N-methylcarbamoyl group, an N-(2-carboxyethyl)-N-methylcarbamoyl group, a 3-(trifluoroacetyl)propionylamino group, an N-(2,2-dimethylpropionyl)-N-methylamino group, an N-(2,2-dimethyl-3-hydroxypropionyl)-N-methylamino group, an N-(2-hydroxy-2-methylpropionyl)-N-methylamino group), (11) —NR^(b8)R^(b9) wherein R^(b8) and R^(b9) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group), (12) —NR^(b10)—C(═O)—R^(b11) wherein R^(b10) and R^(b11) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group), or (13) —O—C(═O)—NR^(b14)R^(b15) wherein R^(b14) and R^(b15) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group),

R^(c) is

(1) a hydrogen atom, (2) a halogen atom (particularly, a fluorine atom, a chlorine atom), (3) a methyl group, (4) —C(═O)—OR^(c1) wherein R^(c1) is a hydrogen atom or a methyl group, (5) —OR^(c2) wherein R^(c2) is a hydrogen atom, a methyl group or an ethyl group,

(6) —NH₂, or

(7) —NR^(c5)—C(═O)—R^(c6) wherein R^(c5) and R^(c6) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group, an isopropyl group), particularly a hydrogen atom,

R^(m) is

(1) a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E, (2) a C₁₋₆ alkyl group substituted by a C₆₋₁₀ aryl group optionally substituted by the same or different 1 to 5 substituents selected from group F, (3) a C₁₋₆ alkyl group substituted by a C₃₋₁₀ cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (4) a C₁₋₆ alkyl group substituted by a C₅₋₁₀ bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (5) a C₁₋₆ alkyl group substituted by a monocyclic aromatic heterocyclic group optionally substituted by the same or different 1 to 5 C₁₋₆ alkyl group (the monocyclic aromatic heterocyclic group contains, besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms), (6) a C₃₋₁₀ cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, or (7) a C₅₋₁₀ bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, more preferably, (1) a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E′, (2) a C₁₋₆ alkyl group substituted by a C₃₋₁₀ cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (3) a C₁₋₆ alkyl group substituted by a C₅₋₁₀ bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (4) a C₃₋₁₀ cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, or (5) a C₅₋₁₀ bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, particularly, (1) a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a neopentyl group) optionally substituted by the same or different 1 to 5 substituents selected from (i) —C(═O)—OR^(E2) wherein R^(E2) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F, (ii) —C(═O)—NR^(E3)R^(E4) wherein R^(E3) and R^(E4) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group, an isopropyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F, (iii) —OR^(E7) wherein R^(E7) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F, and (iv) —NR^(E12)—C(═O)—R^(E13) wherein R^(E12) and R^(E13) are the same or different and each is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F, (2) a C₃₋₁₀ cycloalkyl group (particularly, a cyclohexyl group, a cyclopentyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F (particularly, a hydroxy group, a hydroxymethyl group, a carboxyl group), or (3) a C₅₋₁₀ bridged cycloalkyl group (particularly, an adamantyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F, further particularly, (1) a C₁₋₆ alkyl group (particularly, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a neopentyl group) optionally substituted by the same or different 1 to 5 substituents selected from (i) —C(═O)—OR^(E2) wherein R^(E2) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F, and (ii) —OR^(E7) wherein R^(E7) is a hydrogen atom or a C₁₋₆ alkyl group (particularly, a methyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F, (2) a C₃₋₁₀ cycloalkyl group (particularly, a cyclohexyl group, a cyclopentyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F (particularly, a hydroxy group, a hydroxymethyl group, a carboxyl group), or (3) a C₅₋₁₀ bridged cycloalkyl group (particularly, a 1-adamantyl group) optionally substituted by the same or different 1 to 5 substituents selected from group F, particularly,

is a group represented by the following,

R^(e) is the same or different and each is a fluorine atom, a chlorine atom, a methyl group, or a hydroxymethyl group, n is an integer of 0, or 1 to 2, particularly 0.

As specifically preferable compounds of the compound represented by the formula [I], the following compounds can be mentioned.

-   1-(9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carbonyl)-azetidine-3-carboxylic     acid dimethylamide (compound No. 153) -   1-[2-(5-hydroxy-5-trifluoromethyl-5H-indeno[1,2-b]pyridin-3-yloxy)-ethyl]-pyrrolidin-2-one     (compound No. 430) -   4-hydroxymethyl-2-(1-ethyl-1H-pyrazol-4-yl)-9-trifluoromethyl-9H-fluoren-9-ol     (compound No. 629) -   2-[1-(2,2-dimethyl-propyl)-1H-pyrazol-4-yl]-4-hydroxymethyl-9-trifluoromethyl-9H-fluoren-9-ol     (compound No. 660) -   (−)-2-(1-ethyl-1H-pyrazol-4-yl)-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic     acid amide (compound No. 630) -   2-[1-(2,2-dimethyl-propyl)-1H-pyrazol-4-yl]-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic     acid amide (compound No. 659) -   2-(1-cyclohexylmethyl-1H-pyrazol-4-yl)-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic     acid amide (compound No. 667) -   (+)-2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propane-1,3-diol     (compound No. 595) -   (+)-3-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionic     acid (compound No. 538) -   (+)-4-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-butyric     acid (compound No. 539)

In addition, in the compound represented by the formula [I], various “isomers” are present. When an asymmetric carbon atom is present at the 9-position of the fluorene ring of the compound represented by the formula [I], enantiomers exist as a stereoisomer based thereon, and when an asymmetric carbon atom is further present in a substituent, diastereomers exist.

Specifically, an optical active form of the compound represented by the following chemical formulas and a mixture thereof are encompassed in the present invention.

In addition, an optically active form of the compound represented by the following chemical formulas, which is a preferable embodiment of the compound of the present invention, and a mixture thereof are encompassed in the present invention.

In addition, when E form and Z form exist as geometric isomers, and an axial chirality is present, stereoisomers based on these exist. In some cases, tautomers may exist. Therefore, all of these isomers and mixtures thereof are encompassed in the present invention.

As a compound represented by the formula [III], preferred is a compound represented by the formula [III-A].

As a compound represented by the formula [III-A], preferred is a compound wherein R^(m) is

(1) a C₁₋₆ alkyl group optionally substituted by the same or different 1 to 5 substituents selected from group E′, (2) a C₁₋₆ alkyl group substituted by a C₃₋₁₀ cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (3) a C₁₋₆ alkyl group substituted by a C₅₋₁₀ bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, (4) a C₃₋₁₀ cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F, or (5) a C₅₋₁₀ bridged cycloalkyl optionally substituted by the same or different 1 to 5 substituents selected from group F.

In another embodiment, a specifically preferable compound of the compound represented by the formula [I] is the following compound.

Particularly preferred is the following compound.

A pharmaceutically acceptable salt of the compound represented by the formula [I] (hereinafter to be also referred to as the compound of the present invention) may be any salt as long as it forms a nontoxic salt with the compound of the present invention. Examples thereof include salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, salts with amino acids and the like.

Examples of the salt with inorganic acid include a salt with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like.

Examples of the salt with organic acid include salts with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.

Examples of the salt with inorganic base include sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt and the like.

Examples of the salt with organic base include methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, dicyclohexylamine, N,N′-dibenzylethylenediamine, guanidine, pyridine, picoline, choline, cinchonine, meglumine and the like.

Examples of the salt with amino acid include salts with lysine, arginine, aspartic acid, glutamic acid and the like.

When a salt of the formula [I] is desired, each salt can be obtained by reacting a compound represented by the formula [I] with an inorganic base, organic base, inorganic acid, organic acid or amino acid according to a known method.

The “solvate” is a compound represented by the formula [I] or a pharmaceutically acceptable salt thereof wherein a molecule of the solvent is coordinated, and also includes hydrates. As the solvate, a pharmaceutically acceptable solvate is preferable and includes, for example, hydrate, ethanolate, dimethylsulfoxidate and the like of the compound represented by the formula [I] or a pharmaceutically acceptable salt thereof. Specific examples thereof include hemihydrate, monohydrate, dihydrate and monoethanolate of the compound represented by the formula [I], monohydrate of sodium salt, 2/3 ethanolate of dihydrochloride, and the like of the compound represented by the formula [I].

The solvate can be obtained according to a method known per se.

In addition, the compound represented by the formula [I] may be labeled with an isotope (e.g., ³H, ¹⁴C, ³⁵S etc.).

The deuterium derivative wherein ¹H of the compound represented by the formula [I] is substituted with ²H(D) is also encompassed in the compound represented by the formula [I].

As the compound represented by the formula [I] or a pharmaceutically acceptable salt thereof or a solvate thereof, a compound represented by the formula [I] or a pharmaceutically acceptable salt thereof or a solvate thereof, each of which is substantially purified, is preferable. More preferred is, a compound represented by the formula [I] or a pharmaceutically acceptable salt thereof or a solvate thereof, each of which is purified to a purity of not less than 80%.

In the present invention, a prodrug of the compound represented by the formula [I] can also be a useful medicament. The “prodrug” is a derivative of the compound of the present invention having a chemically or metabolically degradable group which, after administration to the body, restores to the original compound by, for example, hydrolysis, solvolysis or decomposition under physiological conditions, and shows inherent efficacy. It is considered to include a noncovalent complex, and a salt. Prodrug is utilized for, for example, improvement of absorption on oral administration, or targeting to a target moiety.

Examples of the modified moiety include, in the compound of the present invention, a highly reactive functional group such as a hydroxyl group, a carboxyl group, an amino group and the like.

Specific examples of the hydroxyl-modifying group include an acetyl group, a propionyl group, an isobutyryl group, a pivaloyl group, a palmitoyl group, a benzoyl group, a 4-methylbenzoyl group, a dimethylcarbamoyl group, a dimethylaminomethylcarbonyl group, a sulfo group, an alanyl group, a fumaryl group, a 3-carboxybenzoyl group, a 2-carboxyethylcarbonyl group and the like. In addition, sodium salt of 3-carboxybenzoyl group, 2-carboxyethylcarbonyl group and the like can be mentioned.

Specific examples of the carboxyl-modifying group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pivaloyloxymethyl group, a carboxymethyl group, a dimethylaminomethyl group, a 1-(acetyloxy)ethyl group, a 1-(ethoxycarbonyloxy)ethyl group, a 1-(isopropyloxycarbonyloxy)ethyl group, a 1-(cyclohexyloxycarbonyloxy)ethyl group, a (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, a benzyl group, a phenyl group, an o-tolyl group, a morpholinoethyl group, an N,N-diethylcarbamoylmethyl group, a phthalidyl group and the like.

Specific examples of the amino-modifying group include a tert-butyl group, a docosanoyl group, a pivaloyloxymethyl group, an alanyl group, a hexylcarbamoyl group, a pentylcarbamoyl group, a 3-methylthio-1-(acetylamino)propylcarbonyl group, a 1-sulfo-1-(3-ethoxy-4-hydroxyphenyl)methyl group, a (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, a (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonyl group, a tetrahydrofuranyl group, a pyrrolidylmethyl group and the like.

Examples of the “pharmaceutical composition” include oral preparations such as tablet, capsule, granule, powder, troche, syrup, emulsion, suspension and the like, and parenteral agents such as external preparation, suppository, injection, eye drop, nasal preparation, pulmonary preparation and the like.

The pharmaceutical composition of the present invention is produced according to a method known in the art of pharmaceutical preparations, by mixing a compound represented by the formula [I] or a pharmaceutically acceptable salt thereof or a solvate thereof with a suitable amount of at least one kind of pharmaceutically acceptable carrier and the like as appropriate. While the content of the compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof in the pharmaceutical composition varies depending on the dosage form, dose and the like, it is, for example, 0.1 to 100 wt % of the whole composition.

Examples of the “pharmaceutically acceptable carrier” include various organic or inorganic carrier substances conventionally used as preparation materials, for example, excipient, disintegrant, binder, fluidizer, lubricant and the like for solid preparations, and solvent, solubilizing agent, suspending agent, isotonicity agent, buffering agent, soothing agent and the like for liquid preparations. Where necessary, moreover, additives such as preservative, antioxidant, colorant, sweetening agent and the like are used.

Examples of the “excipient” include lactose, sucrose, D-mannitol, D-sorbitol, cornstarch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, gum arabic and the like.

Examples of the “disintegrant” include carmellose, carmellose calcium, carmellose sodium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose and the like.

Examples of the “binder” include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, gum arabic and the like.

Examples of the “fluidizer” include light anhydrous silicic acid, magnesium stearate and the like.

Examples of the “lubricant” include magnesium stearate, calcium stearate, talc and the like.

Examples of the “solvent” include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.

Examples of the “solubilizing agents” include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate and the like.

Examples of the “suspending agent” include benzalkonium chloride, carmellose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose, glycerol monostearate and the like.

Examples of the “isotonicity agent” include glucose, D-sorbitol, sodium chloride, D-mannitol and the like.

Examples of the “buffering agent” include sodium hydrogenphosphate, sodium acetate, sodium carbonate, sodium citrate and the like.

Examples of the “soothing agent” include benzyl alcohol and the like.

Examples of the “preservative” include ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid and the like.

Examples of the “antioxidant” include sodium sulfite, ascorbic acid and the like.

Examples of the “colorant” include food colors (e.g., Food Color Red No. 2 or 3, Food Color yellow No. 4 or 5 etc.), β-carotene and the like.

Examples of the “sweetening agent” include saccharin sodium, dipotassium glycyrrhizinate, aspartame and the like.

The pharmaceutical composition of the present invention can be administered orally or parenterally (e.g., topical, rectal, intravenous administration etc.) to human as well as mammals other than human (e.g., mouse, rat, hamster, guinea pig, rabbit, cat, dog, swine, bovine, horse, sheep, monkey etc.). The dose varies depending on the subject of administration, disease, symptom, dosage form, administration route and the like. For example, the daily dose for oral administration to an adult patient (body weight: about 60 kg) is generally within the range of about 1 mg to 1 g, based on the compound of the present invention as the active ingredient. This amount can be administered in one to several portions.

The compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof has inhibitory activity against pyruvate dehydrogenase kinase (PDHK, particularly PDHK2), and can activate pyruvate dehydrogenase (PDH) effectively. Therefore, the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof can be used as an active ingredient of an agent for the treatment or prophylaxis of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer. Furthermore, the compound can be used as an active ingredient of an agent for the treatment or prophylaxis of diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), cerebral ischemia, cerebral apoplexy or pulmonary hypertension.

To “inhibit PDHK” means to specifically inhibit the function of PDHK and eliminate or attenuate the activity. To “inhibit PDHK”, human PDHK is preferably inhibited. As a “PDHK inhibitor”, preferred is a “human PDHK inhibitor”.

To “inhibit PDHK2” means to specifically inhibit the function of PDHK2 and eliminate or attenuate the activity. For example, it means to specifically inhibit the function as PDHK2 based on the conditions in the below-mentioned Experimental Example 1. To “inhibit PDHK2”, human PDHK2 is preferably inhibited. As a “PDHK2 inhibitor”, preferred is a “human PDHK2 inhibitor”.

To “activate PDH” means to activate PDH in a target organ (e.g., liver, skeletal muscle, adipose tissue, heart, brain) and the like, cancer or the like.

To “decrease blood glucose level” means to decrease the glucose concentration in blood (including in serum and plasma), preferably to decrease high blood glucose level, more preferably, to decrease the blood glucose level to normal level for human.

The above-mentioned compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof can be used in combination with one or a plurality of other medicaments (hereinafter to be also referred to as a concomitant drug) according to a method generally employed in the medical field (hereinafter to be referred to as combined use).

The administration period of the above-mentioned compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a concomitant drug is not limited, and they may be administered to an administration subject as combination preparation, or the both preparations may be administered simultaneously or at given intervals. In addition, the pharmaceutical composition of the present invention and a concomitant drug may be used as a medicament in the form of a kit. The dose of the concomitant drug is similar to the clinically-employed dose and can be appropriately selected according to the subject of administration, disease, symptom, dosage form, administration route, administration time, combination and the like. The administration form of the concomitant drug is not particularly limited, and it only needs to be combined with the compound of the present invention or a salt thereof, or a solvate thereof.

Examples of the concomitant drug include an agent for the treatment and/or prophylaxis of diabetes and the like, and 1 to 3 agents therefrom and the compound represented by the formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof can be used in combination.

Examples of the “agent for the treatment and/or prophylaxis of diabetes” include insulin preparation, sulfonylurea hypoglycemic agent and the like.

In the following, one example of the production method of the compound to be used for the embodiment of the present invention is explained. However, the production method of the compound of the present invention is not limited thereto.

Even if no directly corresponding disclosure is found in the following Production Methods, the steps may be modified for efficient production of the compound, such as introduction of a protecting group into a functional group with deprotection in a subsequent step, subjecting a functional group as a precursor to each step, followed by conversion to a desired functional group at a suitable stage, changing the order of Production Methods and steps, and the like.

The treatment after reaction in each step may be conventional ones, where isolation and purification can be performed as necessary according to a method appropriately selected from conventional methods such as crystallization, recrystallization, distillation, partitioning, silica gel chromatography, preparative HPLC and the like, or a combination of those methods.

Production Method 1 (Production Method of a Compound Represented by the Formula [I])

wherein each symbol is as defined above.

(Step 1)

Compound [Ia] is reacted with trimethyl(trifluoromethyl)silane in a solvent in the presence of a catalyst to allow trifluoromethylation to give trimethylsilyl ether of compound [1]. Then, the obtained trimethylsilyl ether is hydrolyzed to give compound [1] as a racemate.

Examples of the solvent to be used for the reaction include amide solvents such as dimethylformamide, N,N-dimethylacetamide etc. and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is dimethylformamide.

Examples of the catalyst to be used for the trifluoromethylation reaction include alkali metal carbonates such as potassium carbonate and the like; alkali metal acetates such as lithium acetate and the like; fluorides such as tetrabutylammonium fluoride etc., and the like. Preferred is potassium carbonate or lithium acetate.

The reaction temperature of the trifluoromethylation is generally about 0 to 50° C., preferably about 0° C. to room temperature.

The reaction time of the trifluoromethylation is generally about 30 min to 1 day, preferably about 30 min to 3 hr.

The amount of trimethyl(trifluoromethyl)silane to be used is generally about 1 to 5 mol, preferably about 1 to 2.5 mol, per 1 mol of compound [Ia].

The amount of the catalyst of the trifluoromethylation reaction to be used is generally about 0.01 to 1 mol, preferably about 0.05 to 0.5 mol, per 1 mol of compound [Ia].

Examples of the reagent to be used for the hydrolysis of trimethylsilyl ether include alkali metal fluorides such as cesium fluoride and the like; ammonium fluoride salts such as tetrabutylammonium fluoride etc., and the like.

When trimethylsilyl ether is hydrolyzed, the reaction temperature is generally about −10 to 50° C., preferably about 0° C. to room temperature.

When trimethylsilyl ether is hydrolyzed, the reaction time is generally about 1 min to 1 day, preferably about 5 min to 2 hr.

The amount of the reagent to be used for the hydrolysis of trimethylsilyl ether is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [Ia].

When optically active compound [I] is desired, the desired optically active compound [I] can be obtained by separating racemate according to preferential crystallization method, diastereomer method, optical resolution method using chiral stationary phase column and the like.

Production Method 2 (Production Method of a Compound Represented by the Formula [II] Wherein Y^(d) is a Single Bond (Compound [IIo]))

wherein “Hal¹” is a halogen atom, preferably a bromine atom, a chlorine atom or an iodine atom; “Hal²” is a halogen atom, preferably a chlorine atom or a bromine atom; “R^(Y1)” and “R^(Y2)” are the same or different and each is a carboxyl-protecting group such as a C₁₋₄ alkyl group (e.g., a methyl group, an ethyl group, t-butyl etc.), a benzyl group and the like; at least one of the substituents “R^(Z1)” to “R^(Z3)” of amine has an asymmetric center and a single steric configuration (e.g., (R)-1-phenylethyl-1-yl, (S)-1-phenylethyl-1-yl, (R)-1-(1-naphthyl)ethyl-1-yl, (S)-1-(1-naphthyl)ethyl-1-yl etc.), and the rest is, for example, a hydrogen atom, alkyl groups such as a methyl group, an ethyl group and the like, an optionally substituted aralkyl group such as a benzyl group and the like, and the like; “M” is a group including boron, zinc, tin or the like, for example, boronic acid, dialkoxyboron, halogenozinc, trialkyltin and the like; the substituent “R^(X)” of the boron compound is, for example, a hydrogen atom, an alkyl group such as a methyl group and the like, or when it is “—B(OR^(X))₂”, two R^(X), oxygen atoms and a boron atom bonded thereto in combination optionally form 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl or the like; “R^(k0)” is a substituent capable of conversion to “R^(k)” (e.g., (cyclo)alkyl group etc. substituted by carboxylic acid, carboxamide, alcohol etc.) by various functional group conversion reactions (e.g., (cyclo)alkyl group etc. substituted by ester, ether etc.); “*” is an asymmetric center; a compound having “*” is an optically active form; a compound having “(*)” is a racemate or an optically active form; and other symbols are as defined above.

(Step 10)

Compound [IIa] is reacted with compound [IIb] in a solvent in the presence of a metal catalyst and a base to give compound [IIc].

Here, M of compound [IIb] is a group containing boron, zinc, tin or the like. Examples thereof include boronic acid, dialkoxyboron, halogenozinc, trialkyltin and the like. Preferred are dialkoxyboron and boronic acid, and particularly preferred is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl.

Examples of the solvent to be used for the reaction include hydrocarbon solvents such as toluene and the like; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like; amide solvents such as dimethylformamide and the like; dimethyl sulfoxide; water and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is a mixed solvent of toluene and water.

Examples of the metal catalyst to be used for the reaction include those having palladium or nickel, and preferred are palladium, particularly preferably palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride, tetrakis(triphenylphosphine)palladium(0).

The amount of the metal catalyst to be used is generally about 0.001 to 1 mol, preferably about 0.01 to 0.2 mol, per 1 mol of compound [IIa].

Examples of the base to be used for the reaction include alkali metal phosphates such as tripotassium phosphate and the like; alkali metal carbonates such as sodium carbonate and the like; alkali metal acetate such as sodium acetate and the like; organic bases such as triethylamine and the like, preferably tripotassium phosphate.

The reaction temperature is generally about room temperature to 120° C., preferably about 90 to 110° C.

The reaction time is generally about 30 min to 1 day, preferably about 1-2 hr.

The amount of compound [IIb] to be used is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [IIa].

The amount of the base to be used is generally about 1 to 5 mol, preferably about 1.5 to 3 mol, per 1 mol of compound [IIa].

(Step 11)

Compound [IId] can be obtained by subjecting compound [IIc] to ester hydrolysis in a solvent.

The ester hydrolysis may be performed under general conditions, for example, under alkaline conditions or acidic conditions.

When the hydrolysis is performed under alkaline conditions, compound [IIc] is reacted, for example, in the presence of about 1 to 20 mol of a base (alkali metal hydroxide such as potassium hydroxide, sodium hydroxide, lithium hydroxide etc., and the like) per 1 mol of compound [IIc] in, for example, water; alcohol solvents such as methanol, ethanol and the like; ether solvents such as tetrahydrofuran, dioxane etc., and the like, or a mixed solvent of two or more kinds thereof generally at about 0° C. to 100° C. for about 30 min to 1 day.

For reaction under acidic conditions, compound [IIc] is reacted in the presence of, for example, about 0.1 to 100 mol of an acid (hydrochloric acid, sulfuric acid etc.) per 1 mol of compound [IIc] in, for example, water; carboxylic acid solvents such as acetic acid and the like; ether solvents such as tetrahydrofuran, dioxane, etc., and the like, or a mixed solvent of two or more kinds thereof generally at about 0° C. to 100° C. for about 30 min to 2 days.

(Step 12)

Compound [IIe] can be obtained by cyclization reaction of compound [IId] in the presence of an acid without solvent or in a solvent.

Examples of the acid to be used for the reaction include phosphorus pentoxide, polyphosphoric acid and the like. The amount thereof to be used is generally about 1 mol to a large excess per 1 mol of compound [IId]. In addition, when a solvent is used, for example, methanesulfonic acid, sulfuric acid and the like can be mentioned. This reaction is preferably performed without a solvent or in methanesulfonic acid as a solvent.

The reaction temperature is generally about 50 to 200° C., preferably about 80 to 180° C.

The reaction time is generally about 30 min to 1 day, preferably about 1-3 hr.

(Step 13)

Compound [IIe] is reacted with trimethyl(trifluoromethyl)silane in a solvent in the presence of a catalyst to allow a trifluoromethylation reaction to give trimethylsilyl ether of compound [IIf], and the produced trimethylsilyl ether is hydrolyzed to give compound [IIf] as a racemate.

Examples of the solvent to be used for the reaction include amide solvents such as dimethylformamide, N,N-dimethylacetamide etc., and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is dimethylformamide.

Examples of the catalyst to be used for the trifluoromethylation reaction include alkali metal carbonates such as potassium carbonate and the like; alkali metal acetates such as lithium acetate and the like; fluorides such as tetrabutylammonium fluoride etc., and the like. Preferred is potassium carbonate or lithium acetate.

The reaction temperature of the trifluoromethylation is generally about 0 to 50° C., preferably about 0° C. to room temperature.

The reaction time of the trifluoromethylation is generally about 30 min to 1 day, preferably about 30 min to 3 hr.

The amount of trimethyl(trifluoromethyl)silane to be used is generally about 1 to 5 mol, preferably about 1 to 2.5 mol, per 1 mol of compound [IIe].

The amount of the catalyst for the trifluoromethylation reaction to be used is generally about 0.01 to 1 mol, preferably about 0.05 to 0.5 mol, per 1 mol of compound [IIe].

Examples of the reagent to be used for hydrolysis of trimethylsilyl ether include alkali metal fluoride such as cesium fluoride and the like; ammonium fluoride salt such as tetrabutylammonium fluoride etc., and the like.

When trimethylsilyl ether is hydrolyzed, the reaction temperature is generally about −10 to 50° C., preferably about 0° C. to room temperature.

When trimethylsilyl ether is hydrolyzed, the reaction time is generally about 1 min to 1 day, preferably about 5 min to 2 hr.

The amount of the reagent to be used for hydrolysis of trimethylsilyl ether is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [IIe].

(Step 14)

As a method for obtaining optically active compound [IIf], a method comprising steps 14a-14e from compound [IIe] or compound [IIf] can be mentioned. By selecting an appropriate optically active amine for this method, (+) or (−) form of compound [IIf] can be produced.

(Step 14a)

Compound [IIg] wherein an acetic acid ester moiety is introduced can be obtained by trifluoromethylation reaction and hydrolysis of trimethylsilyl ether in the same manner as in Step 13, followed by reaction with halogenated acetic acid ester.

Examples of the halogen atom of halogenated acetic acid ester to be used include a chlorine atom, a bromine atom and an iodine atom. In addition, examples of the carboxyl-protecting group (R^(Y2)) include methyl, ethyl, t-butyl and the like. In this reaction, the halogenated acetic acid ester is preferably ethyl bromoacetate.

This acetic acid ester introduction reaction is performed by directly adding halogenated acetic acid ester to a mixture of the trifluoromethylation reaction product and the trimethylsilyl ether hydrolysis product.

The reaction temperature is generally about 0 to 50° C., preferably about 15 to 30° C.

The reaction time is generally about 30 min to 1 day, preferably about 1 hr to 5 hr.

The amount of the halogenated acetic acid ester to be used is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [IIe].

(Step 14a-2)

Compound [IIg] wherein an acetic acid ester moiety is introduced can also be obtained by reacting isolated compound [IIf] with halogenated acetic acid ester. The reaction for introducing acetic acid ester is performed by reacting compound [IIf] with halogenated acetic acid ester in the presence of 1-5 equivalents (preferably, 2 equivalents) of a base (e.g., potassium carbonate etc.) at 0° C.-80° C. (preferably, room temperature) for 1-24 hr (preferably, overnight).

(Step 14b)

Compound [IIh] can be obtained by general ester hydrolysis of compound [IIg] in the same manner as in Step 11 in a solvent.

(Step 14c)

Compound [IIi], which is a salt of a single diastereomer, can be obtained as a solid by mixing compound [IIh] with an optically active amine in a solvent.

Examples of the optically active amine to be used include (R)-(+)-1-phenylethylamine, (S)-(−)-1-phenylethylamine, (R)-(+)-1-(1-naphthyl)-ethylamine, (S)-(−)-1-(1-naphthyl)-ethylamine and the like.

The amount of the optically active amine to be used is generally about 0.1 to 1 mol, preferably about 0.4 to 0.6 mol, per 1 mol of compound [IIh].

Examples of the solvent to be used include ketone solvents such as methyl ethyl ketone, methyl isobutyl ketone and the like; ester solvents such as ethyl acetate and the like; ether solvents such as isopropyl ether etc., and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this step is methyl ethyl ketone, methyl isobutyl ketone.

The temperature for mixing is generally about 0 to 100° C., preferably about 20 to 70° C.

The time for the mixing is generally about 1 hr to 10 days, preferably about 1 to 5 days.

(Step 14d)

Compound [IIj] can be obtained by treating compound [IIi] with an acidic aqueous solution in a solvent to liberate carboxylic acid.

Examples of the solvent to be used include ester solvents such as ethyl acetate and the like; ether solvents such as ethyl ether and the like; hydrocarbon solvents such as toluene etc., and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is ethyl acetate.

Examples of the acidic aqueous solution to be used include hydrochloric acid, sulfuric acid and the like.

The treatment temperature is generally about 0 to 50° C., preferably about 0° C. to room temperature.

The treatment time is generally about 1 min to 2 hr.

The amount of the acidic aqueous solution to be used is generally about 1 mol to large excess per 1 mol of compound [IIi].

(Step 14e)

Optically active compound [IIf] can be obtained by reacting compound [IIj] in a solvent.

Examples of the solvent to be used for the reaction include amide solvents such as dimethylformamide and the like; alcohol solvents such as t-butyl alcohol and the like; ether solvents such as dioxane and the like; hydrocarbon solvents such as toluene and the like and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is a mixed solvent of dimethylformamide and t-butyl alcohol.

The reagent to be used for the reaction is preferably diphenylphosphoryl azide, and the base to be used for the reaction is a tertiary amine such as triethylamine, N-ethyldiisopropylamine and the like.

The reaction temperature is generally about 0 to 150° C., preferably about 0 to 100° C.

The reaction time is generally about 30 min to 1 day, preferably about 30 min to 5 hr.

The amount of diphenylphosphoryl azide to be used is generally about 1 to 3 mol, preferably about 1 to 1.5 mol, per 1 mol of compound [IIj].

The amount of the base to be used is generally about 1 to 3 mol, preferably about 1 to 1.5 mol, per 1 mol of compound [IIj].

(Step 15)

By treating racemic compound [IIf] using a chiral stationary phase column and the like, a desired optically active compound [IIf] can be separated from the other isomer.

(Step 16)

Compound [IIm] can be obtained by introducing R^(k0) into compound [IIk] in a solvent in the presence of a base such as potassium carbonate, cesium fluoride and the like.

For example, when R^(k0) is a (cyclo)alkyl group, compound [IIm] can be obtained by reacting compound [IIk] with (cyclo)alkyl halide such as (cyclo)alkyl iodide and (cyclo)alkyl bromide, (cyclo)alkyl sulfonic acid ester such as (cyclo)alkyl tosylate, or an α,β-unsaturated carbonyl compound such as acrylic acid ester and the like in amide solvents such as dimethylformamide, N,N-dimethylacetamide and the like or acetonitrile.

(Step 17)

Compound [IIn] can be obtained by reacting compound [IIf] in the form of a racemate or an optically active form with compound [IIm] in a solvent in the presence of a metal catalyst, a ligand and a base.

Boronic acid moiety of compound [IIm] is boronic acid per se, or boronic acid ester, preferably 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl.

Examples of the solvent to be used for the reaction include hydrocarbon solvents such as toluene and the like; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like; amide solvents such as dimethylformamide and the like; dimethyl sulfoxide; water and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is a mixed solvent of toluene and water.

The metal catalyst to be used for the reaction is palladium such as palladium(II) acetate, tris(dibenzylideneacetone)dipalladium(0), dichlorobis(triphenylphosphine)palladium(II) and tetrakis(triphenylphosphine)palladium(0), with preference given to palladium(II) acetate.

The amount of the metal catalyst to be used is generally about 0.001 to 1 mol, preferably about 0.01 to 0.2 mol, per 1 mol of compound [IIf].

The ligand to be used for the reaction is phosphine such as triphenylphosphine, tributylphosphine, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl and the like, with preference given to 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl.

Examples of the base to be used for the reaction include alkali metal phosphate such as tripotassium phosphate and the like; alkali metal carbonate such as sodium carbonate and the like; alkali metal hydrogencarbonate such as sodium hydrogencarbonate and the like; alkali metal acetate such as sodium acetate and the like; organic base such as triethylamine and the like, with preference given to tripotassium phosphate.

The reaction temperature is generally about room temperature to 120° C., preferably about 90 to 110° C.

The reaction time is generally about 30 min to 1 day, preferably about 1-3 hr.

The amount of compound [IIm] to be used is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [IIf].

The amount of the ligand to be used is generally about 1 to 5 mol, preferably about 1 to 3 mol, per 1 mol of the metal catalyst.

The amount of the base to be used is generally about 1 to 5 mol, preferably about 1 to 3 mol, per 1 mol of compound [IIf].

(Step 18)

The object compound [IIo] is obtained from compound [IIn] by general functional group conversion or deprotection.

For example, when compound [IIo] contains a hydroxyl group, the compound can be converted by removal of the hydroxyl-protecting group or reduction of an ester thereof, which is a precursor.

For example, in the case of the former, when a hydroxyl group is protected by a benzyl group, the compound can be converted by catalytic hydrogenation reaction. When the hydroxyl group is protected by a silyl group such as t-butyldimethylsilyl group and the like, the compound can be converted by deprotection with tetrabutylammonium fluoride or the like. When diol is protected by a ketal such as acetonide and the like, the compound can be converted by deprotection with acid such as pyridinium p-toluenesulfonate and the like. In the case of the latter, for example, the compound can be converted by a hydride reduction reaction using sodium borohydride, lithium aluminum hydride or the like in a single solvent such as tetrahydrofuran, tetrahydropyran, water and the like or a mixture thereof. Alternatively, conversion is possible by converting ester to carboxylic acid under general hydrolysis conditions, and reducing the acid with a reducing agent such as borane and the like.

Alternatively, compound [IIo] having a hydroxyl group can also be obtained by newly introducing a hydroxyl group. For example, a hydroxymethyl group can be introduced by reacting compound [IIn] having an ester with paraformaldehyde in the presence of a base such as tetrabutylammonium fluoride and the like. Alternatively, compound [IIo] having a hydroxyl group can also be obtained by introducing formyl group by reacting compound [IIn] having an ester with formic acid ester such as ethyl formate, t-butyl formate and the like in the presence of a base such as sodium hydride, potassium t-butoxide and the like, followed by hydride reduction.

When compound [IIo] has a carboxylic acid, compound [IIo] can be obtained by reacting an ester of compound [IIn] in the same manner as in Step 11 under general hydrolysis conditions. For example, when compound [IIn] is t-butyl ester, it can be converted to compound [IIo] under acidic conditions such as trifluoroacetic acid and the like.

When compound [IIo] has a tetrazole ring, the tetrazole ring can be introduced by reacting a cyano group with trimethylsilylazide or the like. A cyano group can be introduced by converting carboxylic acid and the like to an amide and dehydrating the amide with trifluoroacetic anhydride and the like, or by the use of an alkylating agent having a cyano group and the like.

When compound [IIo] has a sulfonamide group, a sulfonamide group can be introduced by amidating an amino group with sulfonyl chloride or the like. The amino group can be introduced by subjecting carboxylic acid to a rearrangement reaction, reacting alkyl halide with an amino source such as phthalimide potassium salt or the like.

The case wherein ring U is pyrazole in the step of obtaining compound [IIo] from compound [IIn] by a functional group conversion is exemplified below.

When Y^(d) is —C(═O)— bond, the compound can be synthesized by an amidation reaction of the corresponding carboxylic acid or an activated derivative thereof with cyclic amine and the like, a reaction with a cyclic organometallic reagent or the like.

For example, various derivatives can be synthesized by the following step.

wherein each symbol is as defined above.

Production Method 3 (Production Method of a Compound Represented by the Formula [IV] Wherein Y^(b) is a Single Bond (Compound [IVn]))

wherein each symbol is as defined above.

(Step 20)

Compound [IVc] can be obtained by reacting compound [IVa] with compound [IVb] in a solvent in the presence of a metal catalyst and a base.

Here, M in compound [IVb] is a group containing boron, zinc, tin or the like and, for example, boronic acid, dialkoxyboron, halogenozinc, trialkyltin and the like can be mentioned. It is preferably dialkoxyboron or boronic acid, particularly preferably 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl.

Examples of the solvent to be used for the reaction include hydrocarbon solvents such as toluene and the like; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like; amide solvents such as dimethylformamide and the like; dimethyl sulfoxide; water and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is a mixed solvent of toluene and water.

A metal catalyst to be used for the reaction is one containing palladium or nickel. Preferred is palladium, particularly preferably palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride or tetrakis(triphenylphosphine)palladium(0).

The amount of the metal catalyst to be used is generally about 0.001 to 1 mol, preferably about 0.01 to 0.2 mol, per 1 mol of compound [IVa].

Examples of the base to be used for the reaction include alkali metal phosphates such as tripotassium phosphate and the like; alkali metal carbonates such as sodium carbonate and the like; alkali metal acetates such as sodium acetate and the like; organic bases such as triethylamine and the like, with preference given to tripotassium phosphate.

The reaction temperature is generally about room temperature to 120° C., preferably about 90 to 110° C.

The reaction time is generally about 30 min to 1 day, preferably about 1-2 hr.

The amount of compound [IVb] to be used is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [IVa].

The amount of the base to be used is generally about 1 to 5 mol, preferably about 1.5 to 3 mol, per 1 mol of compound [IVa].

(Step 21)

Compound [IVd] can be obtained by subjecting compound [IVc] to ester hydrolysis in a solvent.

Ester hydrolysis can be performed under general conditions and, for example, under alkaline conditions or acidic conditions.

When it is performed under alkaline conditions, compound [IVc] is reacted, for example, in the presence of about 1 to 20 mol of a base (alkali metal hydroxide such as potassium hydroxide, sodium hydroxide, lithium hydroxide and the like etc.) per 1 mol of compound [IVc] in, for example, water; alcohol solvents such as methanol, ethanol and the like; ether solvents such as tetrahydrofuran, dioxane, etc., and the like, or a mixed solvent of two or more kinds thereof generally at about 0° C. to 100° C. for about 30 min to 1 day.

When it is performed under acidic conditions, compound [IVc] is reacted, for example, in the presence of about 0.1 to 100 mol of an acid (hydrochloric acid, sulfuric acid etc.) per 1 mol of compound [IVc] in the presence of, for example, water; carboxylic acid solvents such as acetic acid and the like; ether solvents such as tetrahydrofuran, dioxane, etc., and the like, or a mixed solvent of two or more kinds thereof generally at about 0° C. to 100° C. for about 30 min to 2 days.

(Step 22)

Compound [IVe] can be obtained by reacting compound [IVd] to cyclization in the presence of an acid with or without a solvent.

Examples of the acid to be used for the reaction include phosphorus pentoxide, polyphosphoric acid and the like. The amount thereof to be used is generally about 1 mol to a large excess, per 1 mol of compound [IVd]. When a solvent is used, for example, methanesulfonic acid, sulfuric acid and the like can be mentioned. This reaction is preferably performed without solvent or in methanesulfonic acid as a solvent.

The reaction temperature is generally about 50 to 200° C., preferably about 80 to 180° C.

The reaction time is generally about 30 min to 1 day, preferably about 1-3 hr.

(Step 23)

Compound [IVe] is reacted with trimethyl(trifluoromethyl)silane in a solvent in the presence of a catalyst to perform a trifluoromethylation reaction to give a trimethylsilyl ether of compound [IVf], then the resulting trimethylsilyl ether is hydrolyzed to give compound [IVf] as a racemate.

Examples of the solvent to be used for the reaction include amide solvents such as dimethylformamide, N,N-dimethylacetamide and the like and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is dimethylformamide.

Examples of the catalyst to be used for the trifluoromethylation reaction include alkali metal carbonates such as potassium carbonate and the like; alkali metal acetates such as lithium acetate and the like; fluorides such as tetrabutylammonium fluoride and the like and the like, with preference given to potassium carbonate or lithium acetate.

The reaction temperature of trifluoromethylation is generally about 0 to 50° C., preferably about 0° C. to room temperature.

The reaction time of trifluoromethylation is generally about 30 min to 1 day, preferably about 30 min to 3 hr.

The amount of trimethyl(trifluoromethyl)silane to be used is generally about 1 to 5 mol, preferably about 1 to 2.5 mol, per 1 mol of compound [IVe].

The amount of the catalyst to be used for the trifluoromethylation reaction is generally for about 0.01 to 1 mol, preferably about 0.05 to 0.5 mol, per 1 mol of compound [IVe].

Examples of the reagent to be used for trimethylsilyl ether hydrolysis include alkali metal fluoride such as cesium fluoride and the like; ammonium fluoride salts such as tetrabutylammonium fluoride and the like and the like.

The reaction temperature when trimethylsilyl ether is hydrolyzed is generally about −10 to 50° C., preferably about 0° C. to room temperature.

The reaction time when trimethylsilyl ether is hydrolyzed is generally about 1 min to 1 day, preferably about 5 min to 2 hr.

The amount of the reagent to be used for trimethylsilyl ether hydrolysis is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [Ive].

(Step 24)

Compound [IVg] can be obtained by reacting compound [IVf] in a solvent in the presence of an oxidant.

Examples of the solvent to be used for the reaction include water, pyridine, t-butyl alcohol, acetone, acetic acid, sulfuric acid and the like. They can be used alone or in a mixture with water. Preferable solvent for this reaction is a mixed solvent of water and pyridine.

Examples of the oxidant to be used for the reaction include permanganates such as potassium permanganate and the like, chromates such as sodium chromate and the like and the like, with preference given to potassium permanganate.

The reaction temperature is generally about 0 to 120° C., preferably 50 to 110° C.

The reaction time is generally about 30 min to 1 day, preferably about 1 to 8 hr.

The amount of potassium permanganate to be used is generally about 2 to 20 mol, preferably about 2 to 10 mol, per 1 mol of compound [IVf].

(Step 25)

As a method for obtaining optically active compound [IVg], a method includes Steps 25a-25b from a racemic compound [IVg]. In this method, (+) or (−) form of compound [IVg] can be produced by appropriately selecting an optically active amine.

(Step 25a)

Compound [IVh], which is a salt of single diastereomer, can be obtained as a solid by mixing compound [IVg] with optically active amine in a solvent.

Examples of the optically active amine to be used include (R)-(+)-1-phenylethylamine, (S)-(−)-1-phenylethylamine, (R)-(+)-1-(1-naphthyl)-ethylamine, (S)-(−)-1-(1-naphthyl)-ethylamine and the like.

The amount of the optically active amine to be used is generally about 0.1 to 1.5 mol, preferably about 0.4 to 1 mol, per 1 mol of compound [IVg].

Examples of the solvent to be used include ester solvents such as ethyl acetate and the like; ether solvents such as isopropyl ether and the like; ketone solvents such as methyl ethyl ketone, methyl isobutyl ketone and the like and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this step is ethyl acetate.

The temperature for mixing is generally about 0 to 100° C., preferably about 15 to 30° C.

The time for mixing is generally about 1 hr to 10 days, preferably about 1 day to 3 days.

(Step 25b)

Optically active compound [IVg] can be obtained by treating compound [IVh] with acidic aqueous solution in a solvent, and liberating carboxylic acid.

Examples of the solvent to be used include ester solvents such as ethyl acetate and the like; ether solvents such as ethyl ether and the like; hydrocarbon solvents such as toluene and the like and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is ethyl acetate.

Examples of the acidic aqueous solution to be used include hydrochloric acid, sulfuric acid and the like.

The treatment temperature is generally about 0 to 50° C., preferably about 0° C. to room temperature.

The treatment time is generally about 1 min to 2 hr.

The amount of the acidic aqueous solution to be used is generally about 1 mol to large excess per 1 mol of compound [IVh].

(Step 26)

By treating racemic compound [IVg] using a chiral stationary phase column and the like, a desired optically active compound [IVg] can be separated from the other isomer.

The chiral stationary phase column to be used is, for example, Daicel, CHIRALCEL OD-RH.

Examples of the solvent for separation include a mixed solution of acetonitrile and phosphate buffer wherein the composition ratio thereof is constant or varied.

For separation, a conventional high performance liquid chromatography apparatus is used, which is performed while monitoring with a detector such as ultraviolet absorption and the like.

(Step 27)

Compound [IVk] can be obtained by introducing R^(j) into compound [IVj] in a solvent in the presence of a base such as potassium carbonate and the like.

For example, when R^(j) is a (cyclo)alkyl group, compound [IVk] can be obtained by reacting compound [IVj] with (cyclo)alkyl halide such as (cyclo)alkyl iodide, (cyclo)alkyl sulfonic acid ester such as (cyclo)alkyl tosylate or the like in amide solvents such as dimethylformamide, N,N-dimethylacetamide and the like or acetonitrile.

(Step 28)

Compound [IVm] can be obtained by reacting compound [IVg] in the form of a racemate or an optically active form with compound [IVk] in a solvent in the presence of a metal catalyst, a ligand and a base.

Boronic acid moiety of compound [IVk] is boronic acid per se, or boronic acid ester, preferably 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl.

Examples of the solvent to be used for the reaction include hydrocarbon solvents such as toluene and the like; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like; amide solvents such as dimethylformamide and the like; dimethyl sulfoxide; water and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is a mixed solvent of dioxane and water.

The metal catalyst to be used for the reaction is palladium, for example, palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II), tetrakis(triphenylphosphine)palladium(0), with preference given to palladium(II) acetate.

The amount of the metal catalyst to be used is generally for about 0.001 to 1 mol, preferably about 0.01 to 0.2 mol, per 1 mol of compound [IVg].

The ligand to be used for the reaction is phosphine such as triphenylphosphine, tributylphosphine, 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl and the like. Preferred is 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl.

Examples of the base to be used for the reaction include alkali metal phosphates such as tripotassium phosphate and the like; alkali metal carbonates such as sodium carbonate and the like; alkali metal acetate such as sodium acetate and the like, with preference given to tripotassium phosphate.

The reaction temperature is generally about room temperature to 120° C., preferably about 90 to 110°.

The reaction time is generally about 30 min to 1 day, preferably about 1-3 hr.

The amount of compound [IVk] to be used is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [IVg].

The amount of the ligand to be used is generally about 1 to 5 mol, preferably about 1 to 3 mol, per 1 mol of the metal catalyst.

The amount of the base to be used is generally about 1 to 5 mol, preferably about 1 to 3 mol, per 1 mol of compound [IVg].

(Step 29)

The object compound [IVn] is obtained from compound [IVm] by general functional group conversion or deprotection.

For example, when compound [IVn] contains carboxamide, the compound can be obtained by reacting carboxylic acid with amine to allow amidation with, for example, a condensation agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the like in the presence of 1-hydroxybenzotriazole hydrate in a solvent such as dimethylformamide, chloroform and the like. In this case, carboxylic acid may be converted in advance to acid chloride, mixed acid anhydride or the like, and reacted with amine to allow amidation, whereby compound [IVn] containing carboxamide can be obtained.

When compound [IVn] has an ester, a general esterification reaction with alcohol needs to be performed. For example, carboxylic acid may be converted in advance to an acid chloride, and reacted with alcohol in the presence of a base such as pyridine and the like without solvent or in chloroform, whereby compound [IVn] having an ester can be obtained. Compound [IVn] having an ester can also be obtained by reacting carboxylic acid with alkyl halide in the presence of a base such as potassium carbonate in, for example, dimethylformamide.

When compound [IVn] contains a hydroxyl group, it can be obtained by reduction of carboxylic acid or a reaction with an organiometalic reagent. In the case of the former, for example, compound [IVn] containing a hydroxyl group can be obtained by performing a hydride reduction reaction using borane, lithium aluminum hydride and the like in a single or mixed solvent of ethyl ether, tetrahydrofuran, tetrahydropyran and the like.

When Y^(b) is an amine bond compound [IVn] wherein Y^(b) is an amine bond can be synthesized by subjecting compound [IVg] to a condensation reaction with amine compound or the like in the presence of a catalyst such as palladium and the like.

When Y^(b) is alkanediyl, compound [IVn] wherein Y^(b) is alkanediyl can be synthesized by subjecting compound [IVg] to a condensation reaction with an organic zinc compound and the like in the presence of a catalyst such as palladium and the like.

When Y^(b) is alkenediyl, compound [IVn] wherein Y^(b) is alkenediyl can be synthesized by subjecting compound [IVg] to a condensation reaction with an alkenylboron compound and the like in the presence of a catalyst such as palladium and the like.

Production Method 4 (Production Method of a Compound Represented by the Formula [IV] Wherein Y^(b) is —C(═O)— Bond (Compound [IVz]))

wherein “R^(Y3)” and “R^(Y4)” are the same or different and each is a carboxyl-protecting group such as a C₁₋₄ alkyl group (e.g., a methyl group, an ethyl group, a t-butyl group etc.), a benzyl group and the like; “R^(j0)” is a substituent (e.g., a carboxyl group etc.) that can be converted to “R^(j)” (e.g., a carbamoyl group etc.) by various functional group conversion reactions, and other symbols are as defined above.

(Step 30)

Compound [IVp] can be obtained by reacting compound [IVo] with compound [IVb] in a solvent, in the presence of a metal catalyst and a base.

Here, M of compound [IVb] is a group containing boron, zinc, tin or the like. Examples thereof include boronic acid, dialkoxyboron, halogenozinc, trialkyltin and the like. Preferred are dialkoxyboron and boronic acid, and particularly preferred is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl.

Examples of the solvent to be used for the reaction include hydrocarbon solvents such as toluene and the like; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like; amide solvents such as dimethylformamide and the like; dimethyl sulfoxide; water and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is a mixed solvent of toluene and water.

Examples of the metal catalyst to be used for the reaction include those having palladium or nickel, and preferred are palladium, and particularly preferred are palladium(II) acetate, dichlorobis(triphenylphosphine)palladium(II), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride, tetrakis(triphenylphosphine)palladium(0).

The amount of the metal catalyst to be used is generally about 0.001 to 1 mol, preferably about 0.01 to 0.2 mol, per 1 mol of compound [IVo].

Examples of the base to be used for the reaction include alkali metal phosphates such as tripotassium phosphate and the like; alkali metal carbonates such as sodium carbonate and the like; alkali metal acetates such as sodium acetate and the like; organic bases such as triethylamine and the like, with preference given to tripotassium phosphate.

The reaction temperature is generally about room temperature to 120° C., preferably about 90 to 110°.

The reaction time is generally about 30 min to 1 day, preferably about 1-2 hr.

The amount of compound [IVb] to be used is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [IVo].

The amount of the base to be used is generally about 1 to 5 mol, preferably about 1.5 to 3 mol, per 1 mol of compound [IVo].

(Step 31)

Compound [IVq] can be obtained by subjecting compound [IVp] to ester hydrolysis in a solvent.

The ester hydrolysis may be performed under general conditions, for example, under alkaline conditions or acidic conditions.

When the hydrolysis is performed under alkaline conditions, compound [IVp] is reacted, for example, in the presence of about 1 to 20 mol of a base (alkali metal hydroxide such as potassium hydroxide, sodium hydroxide, lithium hydroxide etc., and the like) per 1 mol of compound [IVp] in, for example, water; alcohol solvents such as methanol, ethanol and the like; ether solvents such as tetrahydrofuran, dioxane etc., and the like, or a mixed solvent of two or more kinds thereof generally at about 0° C. to 100° C. for about 30 min to 1 day.

For reaction under acidic conditions, compound [IVp] is reacted in the presence of, for example, about 0.1 to 100 mol of an acid (hydrochloric acid, sulfuric acid etc.) per 1 mol of compound [IVp] in, for example, water; carboxylic acid solvents such as acetic acid and the like; ether solvents such as tetrahydrofuran, dioxane, etc., and the like, or a mixed solvent of two or more kinds thereof generally at about 0° C. to 100° C. for about 30 min to 2 days.

(Step 32)

Compound [IVr] can be obtained by cyclization reaction of compound [IVq] in the presence of an acid without solvent or in a solvent.

Examples of the acid to be used for the reaction include phosphorus pentoxide, polyphosphoric acid and the like. The amount thereof to be used is generally about 1 mol to a large excess per 1 mol of compound [IVq]. In addition, when a solvent is used, for example, methanesulfonic acid, sulfuric acid and the like can be mentioned. This reaction is preferably performed without a solvent or in methanesulfonic acid as a solvent.

The reaction temperature is generally about 50 to 200° C., preferably about 80 to 180° C.

The reaction time is generally about 30 min to 1 day, preferably about 1-3 hr.

(Step 33)

Compound [IVs] can be obtained by esterification reaction of compound [IVr] with alkyl halide in a solvent in the presence of a base.

Examples of the solvent to be used for the reaction include amide solvents such as dimethylformamide, N,N-dimethylacetamide and the like; dimethyl sulfoxide; water and the like. Preferable solvent for this reaction is dimethylformamide.

Examples of the base to be used for the reaction include alkali metal carbonates such as potassium carbonate and the like, alkali metal hydrides such as sodium hydride and the like; alkali metal hydroxides such as sodium hydroxide and the like, and the like; with preference given to potassium carbonate.

Examples of the halogen of the alkyl halide to be used for the reaction include iodine, bromine and the like, and examples of the alkyl include methyl, ethyl and the like. Preferred for this step is methyl iodide.

The reaction temperature is generally about 0 to 100° C., preferably about 0 to 80° C.

The reaction time is generally about 10 min to 1 day, preferably about 30 min to 12 hr.

The amount of the base to be used is generally about 1 to 5 mol, preferably about 1 to 3 mol, per 1 mol of compound [IVr].

The amount of the alkyl halide to be used is generally about 1 to 5 mol, preferably about 1 to 3 mol, per 1 mol of compound [IVr].

(Step 34)

Compound [IVs] is reacted with trimethyl(trifluoromethyl)silane in a solvent in the presence of a catalyst to perform a trifluoromethylation reaction to give a trimethylsilyl ether of compound [IVt], then the resulting trimethylsilyl ether is hydrolyzed to give compound [IVt] as a racemate.

Examples of the solvent to be used for the reaction include amide solvents such as dimethylformamide, N,N-dimethylacetamide and the like, and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is dimethylformamide.

Examples of the catalyst to be used for the trifluoromethylation reaction include alkali metal carbonates such as potassium carbonate and the like; alkali metal acetates such as lithium acetate and the like; fluorides such as tetrabutylammonium fluoride and the like; and the like, with preference given to potassium carbonate and lithium acetate.

The reaction temperature of trifluoromethylation is generally about 0 to 50° C., preferably about 0° C. to room temperature.

The reaction time of trifluoromethylation is generally about 30 min to 1 day, preferably about 30 min to 3 hr.

The amount of trimethyl(trifluoromethyl)silane to be used is generally about 1 to 5 mol, preferably about 1 to 2.5 mol, per 1 mol of compound [IVs].

The amount of the catalyst to be used for the trifluoromethylation reaction is generally about 0.01 to 1 mol, preferably about 0.05 to 0.5 mol, per 1 mol of compound [IVs].

Examples of the reagent to be used for the trimethylsilyl ether hydrolysis include alkali metal fluoride such as cesium fluoride and the like; ammonium fluoride salts such as tetrabutylammonium fluoride and the like; and the like.

The reaction temperature when trimethylsilyl ether is hydrolyzed is generally about −10 to 50° C., preferably about 0° C. to room temperature.

The reaction time when trimethylsilyl ether is hydrolyzed is generally about 1 min to 1 day, preferably about 5 min to 2 hr.

The amount of the reagent to be used for trimethylsilyl ether hydrolysis is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [IVs].

(Step 35)

Compound [IVu] can be obtained by subjecting compound [IVt] to ester hydrolysis in a solvent under alkaline conditions.

Examples of the solvent to be used for the reaction include water; alcohol solvents such as methanol, ethanol and the like; ether solvents such as tetrahydrofuran, dioxane and the like; and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvents for this reaction is a mixed solvent of water, methanol and tetrahydrofuran.

Examples of the alkali to be used for the reaction include alkali metal hydroxide such as potassium hydroxide, sodium hydroxide, lithium hydroxide and the like, and the like, with preference given to sodium hydroxide.

The reaction temperature is generally about 0 to 120° C., preferably about 0 to 90° C.

The reaction time is generally about 10 min to 1 day, preferably about 30 min to 12 hr.

The amount of the alkali to be used is generally about 1 mol to large excess, preferably about 1 to 10 mol, per 1 mol of compound [IVt].

(Step 36)

As a method for obtaining optically active compound [IVu], a method includes Steps 36a-36b from a racemic compound [IVu]. In this method, (+) or (−) form of compound [IVu] can be produced by appropriately selecting an optically active amine.

(Step 36a)

Compound [IVv], which is a salt of single diastereomer, can be obtained as a solid by mixing compound [IVu] with an optically active amine in a solvent.

Examples of the optically active amine to be used include (R)-(+)-1-phenylethylamine, (S)-(−)-1-phenylethylamine, (R)-(+)-1-(1-naphthyl)-ethylamine, (S)-(−)-1-(1-naphthyl)-ethylamine and the like.

The amount of the optically active amine to be used is generally about 0.1 to 1.5 mol, preferably about 0.4 to 1 mol, per 1 mol of compound [IVu].

Examples of the solvent to be used include ester solvents such as ethyl acetate and the like; ether solvents such as ethyl ether and the like; and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this step is ethyl acetate.

The temperature for mixing is generally about 0 to 100° C., preferably about 15 to 80° C.

The time for mixing is generally about 1 hr to 10 days, preferably about 1 to 12 hr.

(Step 36b)

Optically active compound [IVu] can be obtained by treating compound [IVv] with acidic aqueous solution in a solvent, and liberating carboxylic acid.

Examples of the solvent to be used include ester solvents such as ethyl acetate and the like; ether solvents such as ethyl ether and the like; hydrocarbon solvents such as toluene and the like and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is ethyl acetate.

Examples of the acidic aqueous solution to be used include hydrochloric acid, sulfuric acid and the like.

The treatment temperature is generally about 0 to 50° C., preferably about 0° C. to room temperature.

The treatment time is generally about 1 min to 2 hr.

The amount of the acidic aqueous solution to be used is generally about 1 mol to large excess per 1 mol of compound [IVv].

(Step 37)

By treating racemic compound [IVu] using a chiral stationary phase column and the like, a desired optically active compound [IVu] can be separated from the other isomer.

The chiral stationary phase column to be used is, for example, Daicel, CHIRALCEL OD-RH.

Examples of the solvent for separation include a mixed solution of acetonitrile and phosphate buffer wherein the composition ratio thereof is constant or varied.

For separation, a conventional high performance liquid chromatography apparatus is used, which is performed while monitoring with a detector such as ultraviolet absorption and the like.

(Step 38)

Compound [IVy] can be obtained by converting a precursor in R^(j0) of compound [IVx] to a functional group in R^(j) of compound [Ivy].

For example, when R^(j) contains amide, compound [IVy] having amide in R^(j) can be obtained by amidation reaction of compound [IVx] having carboxylic acid for R^(j0) with amine in the presence of a condensation agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the like and 1-hydroxybenzotriazole hydrate in a solvent such as dimethylformamide, chloroform and the like.

When a functional group influenced by conversion of a precursor in R^(j0) of compound [IVx] to a functional group in R^(j) of compound [Ivy] is present in other part of compound [IVx], a protecting group may be introduced as appropriate. For example, when an amino group is present in other part during production of compound [IVy] having amide in R^(j) by amidation of compound [IVx] having carboxylic acid for R^(j0), a protecting group such as t-butyloxycarbonyl group, benzyloxycarbonyl group and the like is introduced into the amino group by a conventional method, a desired amidation reaction is performed, and then deprotection is performed by a general method.

(Step 39)

Compound [IVz] can be obtained by reacting compound [IVu], which is a racemate or an optically active form, with compound [IVy].

When compound [IVy] is cyclic amine, compound [IVz] can be obtained by general amidation reaction. For example, compound [IVu] and compound [IVy] are reacted in a solvent in the presence of a condensation agent. Examples of the condensation agent include 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in the copresence of 1-hydroxybenzotriazole hydrate and the like, and examples of the solvent include dimethylformamide, chloroform and the like.

Alternatively, compound [IVu], which is a racemate or an optically active form, may be converted in advance to acid chloride, mixed acid anhydride or the like and reacted with compound [IVy], whereby compound [IVz] can be obtained.

In addition, compound [IVz] is obtained by reacting compound [IVy] with an organic base such as LDA and the like, and reacting the resultant with compound [IVu] or, for example, an amide compound thereof with N,O-dimethylhydroxyamine or the like.

When Y^(b) is an ether bond etc., compound [IVz] wherein Y^(b) is an ether bond etc. can be synthesized by subjecting the corresponding phenol compound to reactions such as Mitsunobu reaction, alkylation reaction with alkyl halide or alkyl sulfonate, and the like.

For example, various derivatives can be synthesized by the following steps.

wherein “Po” is a hydroxyl-protecting group (e.g., a methyl group etc.); and other symbols are as defined above.

Production Method 5 (Production Method of a Compound Represented by the Formula [I] Wherein Xd is a Nitrogen Atom (Compound [V]))

wherein “R^(b00)” is a substituent (e.g., a hydroxy group etc.) that can be converted to “R^(b0)” (e.g., a methoxy group etc.) by various functional group conversion reactions; “R^(b0)” is a substituent (e.g., a methoxy group etc.) that can be converted to “R^(b)” (e.g., carboxamide, an alkoxy group substituted by lactam and the like, an alkyl group etc.) by various functional group conversion reactions; and other symbols are as defined above.

(Step 41)

When a functional group influenced by the reaction in the next Step 42 is present in compound [Va], a protecting group may be introduced into the functional group as appropriate to give compound [Vb].

For example, when the functional group influenced by the reaction is a hydroxyl group, compound [Va] is subjected to alkylation reaction with an alkylating agent in a solvent in the presence of a base to give compound [Vb].

Examples of the solvent to be used for the reaction include amide solvents such as dimethylformamide and the like; ether solvents such as tetrahydrofuran and the like; dimethylsulfoxide and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is dimethylformamide.

Examples of the alkylating agent to be used for the reaction include alkyl halide such as methyl iodide and the like; alkyl sulfonates such as ethyl tosylate and the like; sulfuric acid esters such as methyl sulfate and the like; and the like, with preference given to methyl iodide.

Examples of the base to be used for the reaction include alkali metal carbonates such as potassium carbonate and the like; alkali metal hydrides such as sodium hydride and the like; alkali metal hydroxides such as sodium hydroxide and the like; and the like, with preference given to potassium carbonate.

The reaction temperature is generally about 0 to 120° C., preferably about 0 to 80° C.

The reaction time is generally about 30 min to 1 day, preferably about 1 hr to 1 day.

The amount of the alkylating agent to be used is generally about 1 to 3 mol, preferably about 1 to 2 mol, per 1 mol of compound [Va].

The amount of the base to be used is generally about 1 to 10 mol, preferably about 1 to 5 mol, per 1 mol of compound [Va].

(Step 42)

Compound [Vd] can be obtained by reacting compound [Vb] with compound [Vc] in a solvent in the presence of a metal catalyst and a base.

The boronic acid moiety of compound [Vc] is boronic acid per se, or boronic acid ester, preferably boronic acid per se.

Examples of the solvent to be used for the reaction include hydrocarbon solvents such as toluene and the like; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like; amide solvents such as dimethylformamide and the like; dimethyl sulfoxide; water and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is a mixed solvent of so toluene and water.

Examples of the metal catalyst to be used for the reaction include one containing palladium. Particularly preferred is 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride.

The amount of the metal catalyst to be used is generally about 0.001 to 1 mol, preferably about 0.01 to 0.2 mol, per 1 mol of compound [Vb].

Examples of the base to be used for the reaction include alkali metal phosphates such as tripotassium phosphate and the like; alkali metal carbonates such as sodium carbonate and the like; alkali metal acetates such as sodium acetate and the like, with preference given to tripotassium phosphate.

The reaction temperature is generally about room temperature to 120° C., preferably about 70 to 110° C.

The reaction time is generally about 30 min to 1 day, preferably about 1-3 hr.

The amount of compound [Vc] to be used is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [Vb].

The amount of the base to be used is generally about 1 to 5 mol, preferably about 1.5 to 3 mol, per 1 mol of compound [Vb].

(Step 43)

Compound [Ve] can be obtained by cyclization reaction of compound [Vd] in a solvent in the presence of a base.

Examples of the solvent to be used for the reaction include hydrocarbon solvents such as n-hexane and the like; ether solvents such as tetrahydrofuran and the like; amide solvents such as N-methylpyrrolidone and the like; and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is tetrahydrofuran.

Examples of the base to be used for the reaction include amide bases such as lithium N,N-diisopropylamide, lithium hexamethyldisilazide and the like; organometallics such as butyllithium and the like; and the like, with preference given to lithium N,N-diisopropylamide.

The reaction temperature is generally about −78 to 100° C., preferably about −10 to 50° C.

The reaction time is generally about 10 min to 1 day, preferably about 10 min to 3 hr.

The amount of the base to be used is generally about 1 to 10 mol, preferably about 1 to 3 mol, per 1 mol of compound [Vd].

(Step 44)

Compound [Vf] is obtained from compound [Ve] by general functional group conversion or deprotection.

For example, when R^(b) is a (substituted) alkoxy group and R^(b00) of compound [Va] is a hydroxyl group which is subjected to alkyl group protection in the earlier Step 41, compound [Vf] wherein R^(b) is a (substituted) alkoxy group can be obtained by deprotection to regenerate the hydroxyl group according to a conventional method, for example, by fusing compound [Ve] and pyridinium chloride and the like and, alkylation by, for example, Mitsunobu reaction and the like.

When R^(b) is a (substituted) alkyl group and R^(b00) of compound [Va] is a hydroxyl group which is subjected to alkyl group protection in the earlier Step 41, compound [Vf] wherein R^(b) is a (substituted) alkyl group can be obtained by deprotection according to a conventional method to regenerate the hydroxyl group, conversion to trifluoromethanesulfonate, a reaction of the trifluoromethanesulfonate compound with a terminal acetylene compound or an alkenyl metal compound such as an alkenylboron compound and the like in the presence of a metal catalyst such as palladium and the like, and a hydrogenation reaction.

(Step 45)

Compound [V] can be obtained as a racemate by reacting compound [Vf] with trimethyl(trifluoromethyl)silane in a solvent in the presence of a catalyst to cause trifluoromethylation reaction, whereby a trimethylsilyl ether of compound [V] is obtained, then hydrolyzing the resulting trimethylsilyl ether.

Examples of the solvent to be used for the reaction include amide solvents such as dimethylformamide, N,N-dimethylacetamide and the like, and the like. They can be used alone or two or more kinds thereof may be used in a mixture. Preferable solvent for this reaction is dimethylformamide.

Examples of the catalyst to be used for the trifluoromethylation reaction include alkali metal carbonates such as potassium carbonate and the like; alkali metal acetates such as lithium acetate and the like; fluorides such as tetrabutylammonium fluoride and the like; and the like, with preference given to potassium carbonate and lithium acetate.

The reaction temperature of trifluoromethylation is generally about 0 to 50° C., preferably about 0° C. to room temperature.

The reaction time of trifluoromethylation is generally about 30 min to 1 day, preferably about 30 min to 3 hr.

The amount of trimethyl(trifluoromethyl)silane to be used is generally about 1 to 5 mol, preferably about 1 to 2.5 mol, per 1 mol of compound [Vf].

The amount of the catalyst to be used for the trifluoromethylation reaction is generally for about 0.01 to 1 mol, preferably about 0.05 to 0.5 mol, per 1 mol of compound [Vf].

Examples of the reagent to be used for the trimethylsilyl ether hydrolysis include alkali metal fluorides such as cesium fluoride and the like; ammonium fluoride salts such as tetrabutylammonium fluoride and the like; and the like.

The reaction temperature when trimethylsilyl ether is hydrolyzed is generally about −10 to 50° C., preferably about 0° C. to room temperature.

The reaction time when trimethylsilyl ether is hydrolyzed is generally about 1 min to 1 day, preferably about 5 min to 2 hr.

The amount of the reagent to be used for trimethylsilyl ether hydrolysis is generally about 1 to 5 mol, preferably about 1 to 2 mol, per 1 mol of compound [Vf].

As for compound [V], a desired optically active compound [V] can be separated from the other isomer by a preferential crystallization method, a diastereomer method, an optical resolution method using a chiral stationary phase column, or the like.

EXAMPLES

The production of the compound of the present invention is specifically explained by Examples. However, the present invention is not limited by these Examples.

The room temperature in the Examples means 1-40° C.

(Derivatization Method a for Determination of Optical Purity)

A solid (0.002-0.003 g) to be analyzed is shaken with ethyl acetate (0.1 ml) and 1N hydrochloric acid (0.1 ml), the mixture was stood still to separate layers. The upper layer (0.010 ml) was added to the following preparation solution (0.1 ml), and the mixture was shaken at 50° C. for 30 min. The obtained mixture was analyzed by HPLC.

(Preparation Solution)

Dimethylformamide was added to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.191 g) and 1-hydroxybenzotriazole hydrate (0.153 g) to a total amount of 10 ml. (S)-(−)-1-(1-Naphthyl)-ethylamine (0.258 ml) was added to the mixture to give the title preparation solution.

(10 mM Phosphate Buffer (pH 2.0))

Potassium dihydrogen phosphate (4.08 g) was dissolved in water (3000 mL) and adjusted to pH 2.0 with phosphoric acid to give the title buffer.

HPLC Analysis Conditions Analysis Condition 1

instrument: HPLC system SHIMADZU Corporation high-speed liquid chromatography Prominence column: Daicel CHIRALCEL OD-RH 4.6 mmφ×150 mm column temperature: 40° C. mobile phase: (SOLUTION A) 10 mM phosphate buffer (pH 2.0), (SOLUTION B) acetonitrile the composition (SOLUTION A:SOLUTION B) of the mobile phase was changed linearly from 50:50 to 20:80 over 20 min, thereafter, kept constant at 20:80 for 5 min. flow rate: 0.5 ml/min detection: UV (220 nm)

Analysis Condition 2

instrument: HPLC system SHIMADZU Corporation high-speed liquid chromatography Prominence column: Daicel CHIRALCEL OD-RH 4.6 mmφ×150 mm column temperature: 40° C. mobile phase: (SOLUTION A) 10 mM phosphate buffer (pH 2.0), (SOLUTION B) acetonitrile the composition (SOLUTION A:SOLUTION B) of the mobile phase was changed linearly from 70:30 to 40:60 over 20 min, thereafter, kept constant at 40:60 for 5 min. flow rate: 0.5 ml/min detection: UV (220 nm)

Analysis Condition 3

instrument: HPLC system SHIMADZU Corporation high-speed liquid chromatography Prominence column: Daicel CHIRALCEL OJ-RH 4.6 mmφ×150 mm column temperature: 40° C. mobile phase: (SOLUTION A) 10 mM phosphate buffer (pH 2.0), (SOLUTION B) acetonitrile the composition (SOLUTION A:SOLUTION B) of the mobile phase was kept constant at 70:30 for 25 min, thereafter, at 40:60 for 10 min. flow rate: 0.5 ml/min detection: UV (294 nm)

Analysis Condition 4

instrument: HPLC system SHIMADZU Corporation high-speed liquid chromatography Prominence column: Daicel CHIRALPAK AD-RH 4.6 mmφ×150 mm column temperature: 40° C. mobile phase: (SOLUTION A) 10 mM phosphate buffer (pH 2.0), (SOLUTION B) acetonitrile the composition (SOLUTION A:SOLUTION B) of the mobile phase was changed linearly from 70:30 to 50:50 over 20 min, thereafter, kept constant at 50:50 for 5 min. flow rate: 0.5 ml/min detection: UV (220 nm)

Example 1 Synthesis of (+)-4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-ol (compound No. 526) Step 1

2′-chloro-4′-fluoro-biphenyl-2-carboxylic acid ethyl ester

To a reaction vessel were added 1-bromo-2-chloro-4-fluorobenzene (25 g), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (46 g), toluene (125 ml), water (125 ml) and tripotassium phosphate (50.5 g), and purged with argon. To this mixture was added dichlorobis(triphenylphosphine)palladium(II) (1.67 g) and the mixture was stirred in an oil bath at 110° C. for 3 hr. The oil bath was removed, and water (125 ml) was added to the reaction mixture. The mixture was stirred at room temperature for 1 hr, and filtered through celite. The filtrate was partitioned in a separatory funnel. The aqueous layer was extracted with toluene, and the organic layers were combined. The organic layer was washed twice with water (125 ml), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound (41.8 g). The obtained solid was directly used for the next reaction without further purification.

¹H-NMR (CDCl₃) δ: 8.06-8.02 (1H, m), 7.60-7.54 (1H, m), 7.52-7.45 (1H, m), 7.27-7.16 (3H, m), 7.06-7.00 (1H, m), 4.18-4.09 (2H, m), 1.11-1.06 (3H, m).

Step 2

2′-chloro-4′-fluoro-biphenyl-2-carboxylic acid

To a mixture of ethanol (179 ml) and 2′-chloro-4′-fluoro-biphenyl-2-carboxylic acid ethyl ester (41.8 g) was added 2N aqueous sodium hydroxide solution (179 ml), and the mixture was stirred in an oil bath at 80° C. for 2 hr. The reaction mixture was cooled to room temperature, activated carbon (2.5 g) was added and the mixture was stirred for 2.5 hr. The activated carbon was filtered off through celite and washed with 50 v/v % ethanol-water (100 ml). The filtrate was acidified with 2N hydrochloric acid (196 ml). Then, to this mixture was added water (33 ml) and the mixture was stirred at room temperature for 2 hr. This suspension was filtered, and the obtained solid was air-dried for 2 hr, and dried under reduced pressure at 60° C. to give the title compound (28.6 g, 2 steps 93%).

¹H-NMR (CDCl₃) δ: 8.12-8.08 (1H, m), 7.64-7.59 (1H, m), 7.52-7.47 (1H, m), 7.27-7.24 (1H, m), 7.22-7.16 (2H, m), 7.05-7.00 (1H, m).

Step 3

4-chloro-2-fluoro-fluoren-9-one

To a mixture of phosphorus pentoxide (133 g) and methanesulfonic acid (1300 ml) was added 2′-chloro-4′-fluoro-biphenyl-2-carboxylic acid (132.9 g), and the mixture was stirred at 80° C. for 2.5 hr. The reaction mixture was ice-cooled, water (1300 ml) was slowly added dropwise, and the mixture was further stirred at room temperature for 1 hr. This suspension was filtered, and the obtained solid was washed with water (300 ml). The solid was mixed with 50 v/v % ethanol-water (1300 ml), and the slurry was stirred at room temperature for 1.5 hr, and filtered. The obtained solid was washed with 50 v/v % ethanol-water (200 ml), air-dried for 3 hr, and dried under reduced pressure at 60° C. to give the title compound (121.6 g, 99%).

¹H-NMR (CDCl₃) δ: 8.13-8.10 (1H, m), 7.72-7.69 (1H, m), 7.57-7.53 (1H, m), 7.36-7.30 (2H, m), 7.20-7.17 (1H, m).

Step 4

(4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid ethyl ester

To a mixture of dimethylformamide (1000 ml) and 4-chloro-2-fluoro-fluoren-9-one (204 g) was added potassium carbonate (36.4 g), and the mixture was stirred in a water bath. To this mixture was added dropwise trimethyl(trifluoromethyl)silane (156 ml) over 30 min, and the mixture was further stirred at room temperature for 30 min. To the reaction mixture was added cesium fluoride (173 g), ethyl bromoacetate (75 ml) was added dropwise over 20 min, and the mixture was stirred at room temperature. Water (1000 ml) was added to the reaction mixture, and the mixture was placed in a separatory funnel, and extracted with ethyl acetate (1000 ml). The organic layer was washed twice with brine (water:saturated brine=4:1, 1000 ml) and once with saturated brine (500 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (360 g). The obtained residue was directly used for the next reaction without further purification.

¹H-NMR (CDCl₃) δ: 8.30-8.27 (1H, m), 7.73-7.69 (1H, m), 7.57-7.52 (1H, m), 7.43-7.37 (2H, m), 7.25-7.21 (1H, m), 4.11 (2H, q, J=7.1 Hz), 3.60 (1H, d, J=15.5 Hz), 3.53 (1H, d, J=15.3 Hz), 1.19 (3H, t, J=7.2 Hz).

Step 5

(4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid

To a mixture of ethanol (440 ml) and (4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid ethyl ester (360 g) was added 2N aqueous sodium hydroxide solution (877 ml), and the mixture was stirred at 80° C. for 3.5 hr. The reaction mixture was cooled to room temperature, insoluble material was filtered off through celite, and washed with water (500 ml) and ethanol (60 ml). Water (120 ml) was added to the filtrate and the mixture was ice-cooled, and formic acid (199 ml) was added dropwise. This suspension was stirred at room temperature overnight, and filtered. The obtained solid was washed with 25 v/v % ethanol-water (400 ml), air-dried overnight, and dried under reduced pressure at 60° C. to give the title compound (285 g, 2 steps 90%).

¹H-NMR (CDCl₃) δ: 8.32-8.29 (1H, m), 7.71-7.67 (1H, m), 7.59-7.54 (1H, m), 7.45-7.40 (1H, m), 7.38-7.34 (1H, m), 7.27-7.23 (1H, m), 3.65 (1H, d, J=16.0 Hz), 3.60 (1H, d, J=16.0 Hz).

Step 6

salt of optically active form of (4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid and (R)-(+)-1-(1-naphthyl)-ethylamine

To a mixture of methyl ethyl ketone (250 ml) and (4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid (50 g) was added (R)-(+)-1-(1-naphthyl)-ethylamine (11.1 ml), and the mixture was stirred at 50° C. for 3 days. This suspension was cooled to room temperature, further stirred for 4 days, and filtered. The obtained solid was dried under reduced pressure to give the title compound (25.5 g, 35%). The solid was subjected to derivatization method A for determining the optical purity, and the obtained mixture was analyzed under HPLC analysis condition 1 to find that an isomer with a long retention time was the main component.

isomer with short retention time (retention time 22.58 min) isomer with long retention time (retention time 22.73 min)

Step 7

optically active form of (4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid

To a mixture of ethyl acetate (178 ml), and a salt (25.45 g) of an optically active form of (4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid and (R)-(+)-1-(1-naphthyl)-ethylamine were added 2N hydrochloric acid (51 ml) and water (127 ml), and the mixture was stirred at room temperature for 1 hr. The mixture was partitioned in a separatory funnel. The organic layer was washed twice with water (100 ml) and then with saturated brine (100 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, n-hexane (127 ml) was added to the obtained residue and the mixture was stirred at room temperature for 1 hr. This slurry was filtered, and the obtained solid was washed with hexane, and dried under reduced pressure to give the title compound (16.33 g, 95%).

¹H-NMR (DMSO-D₆) δ: 12.78 (1H, br s), 8.31-8.28 (1H, m), 7.73-7.65 (3H, m), 7.56-7.49 (2H, m), 3.57 (1H, d, J=15.8 Hz), 3.51 (1H, d, J=15.5 Hz).

Step 8

(+)-4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-ol

To a mixture of dimethylformamide (184 ml) and an optically active form (36.74 g) of (4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid was added N-ethyldiisopropylamine (20.9 ml), and the mixture was stirred at 0° C. Thereto, diphenylphosphoryl azide (23.7 ml) was added dropwise over 30 min, and the mixture was further stirred at 0° C. for 2 hr. To the reaction mixture was added acetic acid (2.86 ml) and the mixture was warmed to room temperature. t-Butyl alcohol (96 ml) was added, and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was ice-cooled, 2N hydrochloric acid (367 ml) was added, placed in a separatory funnel and the mixture was extracted 3 times with toluene (180 ml). The combined organic layer was successively washed with water (180 ml), 1N aqueous sodium hydroxide solution (180 ml), water (180 ml) and saturated brine (180 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue, ethanol (37 ml), tetrahydrofuran (37 ml) and 2N aqueous sodium hydroxide solution (37 ml) were mixed, and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was cooled to room temperature, water (180 ml) was added, and the mixture was placed in a separatory funnel, and extracted twice with toluene (180 ml). The organic layer was washed twice with water (180 ml) and once with saturated brine (180 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1 to 8/2) to give the title compound (21.69 g, 70%).

[α]D=+30.60° (20° C., c=1.00, methanol)

¹H-NMR (CDCl₃) δ: 8.29-8.26 (1H, m), 7.73-7.69 (1H, m), 7.55-7.50 (1H, m), 7.43-7.35 (2H, m), 7.21-7.18 (1H, m), 2.82 (1H, s).

Example 2 Synthesis of (+)-2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propane-1,3-diol (compound No. 595) Step 1

[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-acetic acid t-butyl ester

4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (10 g), N,N-dimethylacetamide (100 ml), potassium carbonate (17.8 g) and t-butyl bromoacetate (9.9 ml) were mixed, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was filtered through celite. Water and ethyl ether were added to the filtrate, and the mixture was partitioned in a separatory funnel. The aqueous layer was extracted with ethyl ether, and the organic layers were combined. The organic layer was washed 3 times with water and once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, hexane (50 ml) was added to the obtained residue and the mixture was stirred. This slurry was filtered, and the obtained solid was washed with hexane, and dried under reduced pressure to give the title compound (12.23 g, 77%).

¹H-NMR (DMSO-D₆) δ: 7.92 (1H, d, J=0.7 Hz), 7.59 (1H, d, J=0.5 Hz), 4.95 (2H, s), 1.42 (9H, s), 1.25 (12H, s).

Step 2

optically active form of t-butyl [4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-acetate

Sodium hydrogen carbonate (5.54 g), water (33 ml), toluene (100 ml), (+)-4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-ol (10.0 g), t-butyl [4-(4,4,5,5-tetramethyl-[1,3,2]dioxoborolan-2-yl)-pyrazol-1-yl]-acetate (15.3 g), palladium(II) acetate (370 mg) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.35 g) were mixed, and purged with argon. The mixture was stirred at 100° C. for 180 min. The reaction mixture was cooled to room temperature, water was added, and the mixture was filtered through celite. The filtered substance was further washed with toluene and water. The filtrate was partitioned in a separatory funnel. The aqueous layer was extracted with toluene. The combined organic layer was washed three times with water and once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was recrystallized from n-hexane/2-propanol (10:1, 165 ml) to give the title compound (11.1 g, 60%).

¹H-NMR (CDCl₃) δ: 7.69-7.66 (1H, m), 7.66 (1H, d, J=0.7 Hz), 7.63 (1H, d, J=0.7 Hz), 7.42-7.37 (2H, m), 7.31-7.25 (2H, m), 7.03 (1H, dd, J=9.5, 2.6 Hz), 4.94 (1H, d, J=17.2 Hz), 4.89 (1H, d, J=17.4 Hz), 2.85 (1H, br s), 1.52 (9H, s).

Step 3

optically active form of ethyl 2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-3-oxo-propionate

To a mixture of tetrahydrofuran (80 ml) and an optically active form (10.1 g) of t-butyl [4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-acetate was added ethyl formate (4.13 ml), and the mixture was stirred at 0° C. To this mixture was added sodium hydride (60 w/w % mineral oil dispersion, 2.57 g). The reaction mixture was warmed to room temperature and stirred for 3 hr. The reaction mixture was ice-cooled, 1N hydrochloric acid was added and the mixture was stirred. Ethyl acetate and water were added thereto, and the mixture was partitioned in a separatory funnel. The aqueous layer was further extracted with ethyl acetate, and the extract was combined with the organic layer obtained earlier. The organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (13.2 g). The obtained residue was directly used for the next reaction without further purification.

¹H-NMR (DMSO-D₆) δ: 11.98 (1H, br s), 7.98 (1H, br s), 7.97 (1H, d, J=0.5 Hz), 7.77 (1H, d, J=0.7 Hz), 7.66-7.62 (1H, m), 7.44-7.39 (3H, m), 7.36-7.32 (1H, m), 7.30-7.24 (1H, m), 7.21 (1H, dd, J=9.9, 2.4 Hz), 4.18 (2H, q, J=7.1 Hz), 1.22 (3H, t, J=7.1 Hz).

Step 4

(+)-2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propane-1,3-diol

To a mixture of ethanol (80 ml) and sodium borohydride (16.2 g), a solution of an optically active form (13.2 g) of ethyl 2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-3-oxo-propionate in tetrahydrofuran (80 ml) was added dropwise over 25 min. At this time, the temperature of the reaction mixture was controlled with an ice-bath not to exceed 30° C. The ice-bath was changed to a water-bath, and the mixture was stirred for 17 hr. Then, the water-bath was removed and the mixture was further stirred for 4 hr. The reaction mixture was ice-cooled, 2N hydrochloric acid was added and the mixture was stirred. To this mixture were added ethyl acetate and water, and the mixture was partitioned in a separatory funnel. The aqueous layer was further extracted with ethyl acetate, and the extract was combined with the organic layer obtained earlier. The organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: chloroform/methanol=30/1 to 15/1) to give the title compound (7.38 g, 84%).

[α]D=+67.50° (20° C., c=1.00, methanol)

¹H-NMR (DMSO-D₆) δ: 8.02 (1H, s), 7.68 (1H, s), 7.66-7.61 (1H, m), 7.44-7.37 (3H, m), 7.36-7.31 (1H, m), 7.30-7.26 (1H, m), 7.18 (1H, dd, J=10.0, 2.6 Hz), 4.99-4.94 (2H, m), 4.39-4.32 (1H, m), 3.86-3.76 (4H, m).

The obtained title compound can be crystallized from a solvent (toluene/ethyl acetate (7:1)) containing 1 mol of water per 1 mol of the compound.

Using the above-mentioned (+)-4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-ol as an intermediate and by a similar method, compound Nos. 531, 534, 537, 543, 544, 545, 548, 549, 551, 565, 566, 607, 610, 672, 674, 675, 682, 685, 687, 692, 693, 694, 695, 704 and 705 were synthesized.

Example 3 Synthesis of (+)-3-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionic acid (compound No. 538) Step 1

2′-chloro-4′-methyl-biphenyl-2-carboxylic acid ethyl ester

Under an argon atmosphere, 4-bromo-3-chlorotoluene (200 g), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (376 g), toluene (1000 ml), water (1000 ml), tripotassium phosphate (412 g) and dichlorobis(triphenylphosphine)palladium(II) (14 g) were added to a reaction vessel and the mixture was stirred at 110° C. for 2 hr. The reaction mixture was cooled to room temperature. The insoluble material was filtered off, and washed with water (500 ml) and toluene (500 ml). The filtrate was partitioned in a separatory funnel. The organic layer was washed twice with water (1000 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (337 g). The obtained residue was directly used for the next reaction without further purification.

¹H-NMR (CDCl₃) δ: 8.02-7.99 (1H, m), 7.58-7.53 (1H, m), 7.48-7.43 (1H, m), 7.28-7.23 (2H, m), 7.13-7.11 (2H, m), 4.17-4.08 (2H, m), 2.38 (3H, s), 1.06 (3H, t, J=7.1 Hz).

Step 2

2′-chloro-4′-methyl-biphenyl-2-carboxylic acid

To a mixture of ethanol (728 ml) and 2′-chloro-4′-methyl-biphenyl-2-carboxylic acid ethyl ester (337 g) was added 4N aqueous sodium hydroxide solution (728 ml), and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was cooled to room temperature, activated carbon (17 g) was added and the mixture was stirred overnight. The activated carbon was filtered off, and washed with 50 v/v % ethanol-water (200 ml). The filtrate was acidified by dropwise addition of acetic acid (500 ml) at room temperature. To this mixture, water (414 ml) was added dropwise at room temperature, and the mixture was stirred for 2 hr. This suspension was filtered, and the obtained solid was washed with 40 v/v % ethanol-water (250 ml), and dried under reduced pressure at 80° C. to give the title compound (203 g, 2 steps 85%).

¹H-NMR (DMSO-D₆) δ: 12.60 (1H, br s), 7.93-7.89 (1H, m), 7.64-7.58 (1H, m), 7.53-7.47 (1H, m), 7.32-7.29 (1H, m), 7.25-7.21 (1H, m), 7.20-7.13 (2H, m), 2.34 (3H, s).

Step 3

4-chloro-2-methyl-fluoren-9-one

To a mixture of phosphorus pentoxide (150 g) and methanesulfonic acid (1500 ml) was added 2′-chloro-4′-methyl-biphenyl-2-carboxylic acid (153 g), and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was cooled to 0° C. While keeping the temperature of the reaction mixture at 90° C. or below, water (1500 ml) was added dropwise, and the mixture was further stirred at room temperature for 2 hr. This suspension was filtered, and the obtained solid was washed with water (1000 ml). The solid was suspended in 50 v/v % ethanol-water (1500 ml), and the slurry was stirred at room temperature for 2 hr, and filtered. The obtained solid was air-dried for 1 hr and dried under reduced pressure at 80° C. to give the title compound (140.12 g, 99%).

¹H-NMR (DMSO-D₆) δ: 8.10-8.07 (1H, m), 7.69-7.64 (2H, m), 7.49-7.41 (3H, m), 2.36 (3H, s).

Step 4

(4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid

Under an argon stream, potassium carbonate (18 g) was added to a mixture of dimethylformamide (500 ml) and 4-chloro-2-methyl-fluoren-9-one (100 g). To this mixture, trimethyl(trifluoromethyl)silane (78 ml) was added dropwise over 80 min, and the mixture was further stirred at room temperature for 1 hr. To the reaction mixture was added cesium fluoride (87 g) at room temperature, then ethyl bromoacetate (63 ml) was added dropwise over 15 min, and the mixture was further stirred at room temperature for 4 hr. To the reaction mixture was added water (500 ml), and the aqueous layer was extracted twice with toluene (500 ml). The combined organic layer was washed with water (500 ml) and saturated brine (500 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. To the obtained residue were added ethanol (220 ml) and 2N aqueous sodium hydroxide solution (440 ml), and the mixture was stirred at 80° C. for 1 hr. The reaction mixture was cooled to room temperature, activated carbon (15 g) was added, and the mixture was stirred at room temperature overnight. The activated carbon was filtered off, and washed with 33 v/v % ethanol-water (120 ml). The filtrate was acidified by dropwise addition of acetic acid (151 ml), and the mixture was stirred at room temperature overnight. This suspension was filtered, the obtained solid was washed with 33 v/v % ethanol-water (150 ml), and dried under reduced pressure at 80° C. to give the title compound (136.40 g, 87%).

¹H-NMR (DMSO-D₆) δ: 12.76 (1H, br s), 8.26 (1H, d, J=7.7 Hz), 7.69-7.62 (2H, m), 7.53-7.45 (3H, m), 3.50 (1H, d, J=15.5 Hz), 3.43 (1H, d, J=15.5 Hz), 2.41 (3H, s).

Step 5

salt of optically active form of (4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid and (R)-(+)-1-phenylethylamine

Step 5-1 Synthesis of Seed Crystal

To a mixture of isopropyl ether (16 ml) and (4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid (0.400 g) was added (R)-(+)-1-phenylethylamine (0.058 ml). The mixture was stirred at room temperature for 1 hr 40 min. This suspension was filtered, and the obtained filtrate was dried under reduced pressure to give a solid (0.240 g). The solid (0.210 g) was suspended in ethyl acetate (4.2 ml), and the suspension was stirred at room temperature for 1 hr. This suspension was filtered, and the obtained filtered substance was dried under reduced pressure to give a solid (0.178 g). The solid (0.170 g) was resuspended in ethyl acetate (3.4 ml), and the mixture was stirred at 50° C. for 1 hr. This suspension was filtered, and the obtained solid was dried under reduced pressure to give the title compound (0.137 g). The solid was subjected to derivatization method A for determining the optical purity, and the obtained mixture was analyzed under HPLC analysis condition 1 to find that an isomer with a long retention time was the main component.

isomer with short retention time (retention time 20.19 min) isomer with long retention time (retention time 21.41 min)

Step 5-2

To a mixture of methyl isobutyl ketone (575 ml) and (4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid (191.60 g) was added (R)-(+)-1-phenylethylamine (34.81 ml). To this mixture was added a seed crystal, and the mixture was stirred at 50° C. for 3 days. This suspension was filtered, and the obtained solid was washed with methyl isobutyl ketone (192 ml), and dried under reduced pressure to give the title compound (71.10 g, 28%). The solid was subjected to derivatization method A for determining the optical purity, and the obtained mixture was analyzed under HPLC analysis condition 1 to find that an isomer with a long retention time was the main component.

isomer with short retention time (retention time 24.11 min) isomer with long retention time (retention time 25.43 min)

Step 6

optically active form of (4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid

To a mixture of ethyl acetate (796 ml) and a salt (159.16 g) of an optically active form of (4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid and (R)-(+)-1-phenylethylamine was added 2N hydrochloric acid (318 ml), and the mixture was stirred at room temperature for 2 hr. The mixture was partitioned in a separatory funnel. The organic layer was washed twice with water (600 ml) and once with saturated brine (300 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. n-Hexane was added to the obtained residue and the mixture was stirred at room temperature for 1 hr. This slurry was filtered, and the obtained solid was washed with hexane, and dried under reduced pressure to give the title compound (112.33 g, 95%).

¹H-NMR (DMSO-D₆) δ: 12.75 (1H, br s), 8.26 (1H, d, J=7.7 Hz), 7.71-7.62 (2H, m), 7.54-7.45 (3H, m), 3.50 (1H, d, J=15.5 Hz), 3.43 (1H, d, J=15.5 Hz), 2.41 (3H, s).

Step 7

(+)-4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-ol

To a mixture of dimethylformamide (90 ml) and an optically active form (30 g) of (4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-yloxy)-acetic acid was added triethylamine (14.1 ml), and the mixture was stirred at 0° C. A solution of diphenylphosphoryl azide (20.0 ml) in dimethylformamide (60 ml) was added dropwise over 20 min, and the mixture was further stirred at 0° C. for 2 hr. To the reaction mixture was added t-butyl alcohol (75 ml), and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was ice-cooled, 2N hydrochloric acid (300 ml) was added and the mixture was stirred at room temperature overnight. To this mixture was added water (100 ml) and the mixture was placed in a separatory funnel. The aqueous layer was extracted twice with toluene (300 ml, 200 ml). The combined organic layer was successively washed twice with water (200 ml), twice with 1N aqueous sodium hydroxide solution (150 ml) and once with saturated brine (150 ml), and dried over anhydrous sodium sulfate. Thereto was added silica gel (6 g) and the mixture was stirred at room temperature. The insoluble material was filtered off, and washed with toluene (500 ml). The filtrate was concentrated under reduced pressure to give the title compound (28.58 g).

[α]D=+22.50° (20° C., c=1.00, methanol)

¹H-NMR (CDCl₃) δ: 8.27 (1H, d, J=7.7 Hz), 7.70-7.69 (1H, m), 7.52-7.47 (1H, m), 7.44-7.42 (1H, m), 7.40-7.35 (1H, m), 7.25 (1H, s), 2.82 (1H, br s), 2.41 (3H, s).

Step 8

t-butyl 3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propionate

4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (5.82 g), acetonitrile (50 ml), cesium fluoride (455.7 mg) and t-butyl acrylate (5.7 ml) were mixed at room temperature, and the mixture was stirred at 80° C. for 17.5 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. To the obtained residue were added water and ethyl ether, and the mixture was partitioned in a separatory funnel. The aqueous layer was further extracted with ethyl ether, and the organic layers were combined. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1 to 4/6) to give the title compound (8.38 g, 87%).

¹H-NMR (CDCl₃) δ: 7.77 (1H, s), 7.71 (1H, s), 4.38 (2H, t, J=6.9 Hz), 2.80 (2H, t, J=6.8 Hz), 1.41 (9H, s), 1.31 (12H, s).

Step 9

optically active form of t-butyl 3-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionate

Tripotassium phosphate (35.7 g), water (60 ml), toluene (240 ml), (+)-4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-ol (28.58 g), t-butyl 3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxoborolan-2-yl)-pyrazol-1-yl]-propionate (41.9 g), palladium(II) acetate (1.89 g) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (6.905 g) were mixed in a reaction vessel, and purged with argon. The mixture was stirred at 100° C. for 3 hr. The reaction mixture was cooled to room temperature, water (180 ml) was added and the mixture was stirred overnight. Insoluble material was filtered off through celite, and washed with ethyl acetate (500 ml). The filtrate was partitioned in a separatory funnel. The aqueous layer was extracted with ethyl acetate, and the organic layers were combined. The organic layer was successively washed with water (250 ml), saturated aqueous sodium hydrogen carbonate (250 ml) and saturated brine (200 ml), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was dissolved in toluene/ethyl acetate (3:1, 270 ml). Silica gel (30 g) was added and the mixture was stirred at room temperature for 3 hr. The mixture was filtered, and washed with toluene/ethyl acetate (3:1, 500 ml). The filtrate was concentrated under reduced pressure, isopropyl ether (100 ml) was added to the obtained residue and the mixture was stirred at room temperature for 4 hr. This slurry was filtered, and the obtained solid was washed with isopropyl ether (40 ml), and dried under reduced pressure at 50° C. The solid was mixed with chloroform (27 ml) and the mixture was stirred at room temperature for 5 min. Hexane (107 ml) was added, and the mixture was further stirred for 2 hr 50 min. This suspension was filtered, and the filtered substance was washed with hexane/chloroform (4:1, 40 ml), and dried under reduced pressure at 50° C. to give the title compound (24.75 g, 64%).

¹H-NMR (CDCl₃) δ: 7.69-7.65 (1H, m), 7.54 (1H, s), 7.51-7.47 (1H, m), 7.50 (1H, s), 7.28-7.19 (3H, m), 7.06-7.03 (1H, m), 4.44 (2H, t, J=6.6 Hz), 3.16 (1H, br s), 2.88 (2H, t, J=6.5 Hz), 2.41 (3H, s), 1.43 (9H, s).

Step 10

(+)-3-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionic acid

To a mixture of 1,4-dioxane (6.7 ml) and an optically active form (1.34 g) of t-butyl 3-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionate was added trifluoroacetic acid (6.7 ml), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure. Toluene was added to the obtained residue and the mixture was concentrated under reduced pressure. To the residue was added water (10 ml) and the mixture was extracted twice with ethyl acetate (10 ml). The combined organic layer was washed twice with water (10 ml) and once with saturated brine (10 ml), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the obtained filtrate was concentrated under reduced pressure. Toluene was added to the obtained residue and the mixture was concentrated under reduced pressure. n-Hexane (10 ml) was added to the concentrated residue, and the slurry was stirred and filtered. The obtained solid was washed with n-hexane, and dried under reduced pressure to give the title compound (1.12 g, 96%).

[α]D=+65.10° (25° C., c=1.00, methanol)

¹H-NMR (DMSO-D₆) δ: 12.40 (1H, br s), 7.93 (1H, s), 7.61-7.56 (1H, m), 7.57 (1H, s), 7.41-7.39 (1H, m), 7.30-7.21 (3H, m), 7.13 (1H, br s), 7.09-7.08 (1H, m), 4.40 (2H, t, J=6.6 Hz), 2.87 (2H, t, J=6.6 Hz), 2.36 (3H, s).

Example 4 Synthesis of (+)-4-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-butyric acid (compound No. 539) Step 1

4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-butyric acid ethyl ester

4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (25.0 g), dimethylformamide (200 ml), potassium carbonate (44.5 g) and ethyl 4-bromobutyrate (36.9 ml) were mixed at room temperature and stirred at 75° C. for 6 hr. The reaction mixture was cooled to room temperature, and the insoluble material was filtered off through celite. To the filtrate was added water (150 ml) and the mixture was extracted twice with ethyl acetate (100 ml, 50 ml). To the aqueous layer was added water (100 ml) again and the mixture was extracted twice with ethyl acetate (50 ml). To the combined organic layer was added n-hexane (100 ml), and the mixture was washed 3 times with water (100 ml) and once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate-5/1 to 1/1) to give the title compound (33.4 g, 84%).

¹H-NMR (DMSO-D₆) δ: 7.92 (1H, d, J=0.4 Hz), 7.58 (1H, d, J=0.7 Hz), 4.14 (2H, t, J=6.7 Hz), 4.03 (2H, q, J=7.1 Hz), 2.22 (2H, t, J=7.4 Hz), 2.04-1.96 (2H, m), 1.25 (12H, s), 1.17 (3H, t, J=7.2 Hz).

Step 2

optically active form of 4-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-butyric acid ethyl ester

Tripotassium phosphate (14.86 g), water (30 ml), toluene (60 ml), (+)-4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-ol (9.583 g) and 4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxoborolan-2-yl)-pyrazol-1-yl]-butyric acid ethyl ester (12.08 g) were added to a reaction vessel, and purged with argon. To this mixture were added palladium(II) acetate (314 mg) and a solution (30 ml) of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.149 g) in toluene and the mixture was stirred at 90° C. for 2 hr. The reaction mixture was cooled to room temperature, activated carbon (2 g) was added and the mixture was stirred for 30 min. The insoluble material was filtered off. The filtrate was partitioned in a separatory funnel. The organic layer was washed twice with water (50 ml) and once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was recrystallized from isopropyl ether (50 ml) to give the title compound (7.926 g, 64%).

¹H-NMR (CDCl₃) δ: 7.70-7.66 (1H, m), 7.53-7.51 (1H, m), 7.42 (1H, s), 7.27-7.21 (2H, m), 7.20-7.15 (1H, m), 7.12-7.08 (1H, m), 7.04-7.02 (1H, m), 4.18 (2H, t, J=6.7 Hz), 4.14 (2H, q, J=7.1 Hz), 4.03 (1H, brs), 2.41 (3H, s), 2.34-2.28 (2H, m), 2.23-2.15 (2H, m), 1.25 (3H, t, J=7.2 Hz).

Step 3

(+)-4-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-butyric acid

To a mixture of ethanol (5.4 ml) and an optically active form (3.55 g) of 4-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-butyric acid ethyl ester was added 2N aqueous sodium hydroxide solution (18 ml), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was acidified with 2N hydrochloric acid (36 ml). To this mixture was added water (36 ml), and the mixture was extracted 3 times with ethyl acetate (30 ml). The combined organic layer was washed 3 times with water (50 ml) and once with saturated brine (50 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (3.40 g, 100%).

[α]D=+63.00° (20° C., c=1.00, methanol)

¹H-NMR (DMSO-D₆) δ: 12.21 (1H, br s), 7.98 (1H, s), 7.64-7.59 (1H, m), 7.60 (1H, s), 7.44-7.42 (1H, m), 7.33-7.22 (3H, m), 7.17 (1H, br s), 7.14-7.12 (1H, m), 4.24 (2H, t, J=6.7 Hz), 2.39 (3H, s), 2.27 (2H, t, J=7.3 Hz), 2.12-2.05 (2H, m).

The obtained compound was crystallized from toluene/ethyl acetate (20:1).

Using the above-mentioned (+)-4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-ol as an intermediate and by a similar method, compound Nos. 529, 532, 533, 546, 550, 574, 575, 576, 605, 606, 663, 686, 690, 691, 696, 697, 699, 700, 701, 702, 706 and 707 were synthesized.

Example 5 Synthesis of (−)-2-(1-ethyl-1H-pyrazol-4-yl)-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxamide (compound No. 630) Step 1

ethyl 4′-chloro-2′-methyl-biphenyl-2-carboxylate

Under an argon atmosphere, a mixture of 2-bromo-5-chlorotoluene (20.55 g), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (55.23 g), toluene (200 ml), water (125 ml), tripotassium phosphate (53.07 g) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (1.633 g) was stirred with heating under reflux for 1 hr. The reaction mixture was cooled to room temperature, activated carbon (1 g) was added and the mixture was stirred for 10 min at room temperature. The insoluble material was filtered off, and the filtrate was partitioned in a separatory funnel. The organic layer was washed twice with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=98/2) to give the title compound (27.20 g, 99%).

¹H-NMR (CDCl₃) δ: 7.98 (1H, dd, J=7.7, 1.1 Hz), 7.56-7.51 (1H, m), 7.46-7.42 (1H, m), 7.23-7.22 (1H, m), 7.20-7.16 (2H, m), 7.00 (1H, d, J=7.9 Hz), 4.07 (2H, q, J=7.1 Hz), 2.04 (3H, s), 1.02 (3H, t, J=7.2 Hz).

Step 2

4′-chloro-2′-methyl-biphenyl-2-carboxylic acid

A mixture of ethyl 4′-chloro-2′-methyl-biphenyl-2-carboxylate (27.10 g), ethanol (60 ml) and 1N aqueous sodium hydroxide solution (120 ml) was stirred at 100° C. for 2 hr. To the reaction mixture was added 8N aqueous sodium hydroxide solution (10 ml), and the mixture was further stirred at 100° C. for 1 hr. The reaction mixture was cooled to room temperature. The insoluble material was filtered off, and washed with 33 v/v % ethanol-water (100 ml). The filtrate was adjusted to pH 2 with formic acid (23 ml) and the mixture was stirred at room temperature for 1 hr. This suspension was filtered, and the obtained solid was air-dried for 1 hr and dried under reduced pressure at 60° C. to give the title compound (22.082 g, 91%).

¹H-NMR (DMSO-D₆) δ: 12.64 (1H, s), 7.89 (1H, dd, J=7.8, 1.0 Hz), 7.63-7.58 (1H, m), 7.52-7.48 (1H, m), 7.33-7.32 (1H, m), 7.26-7.19 (2H, m), 7.05 (1H, d, J=8.2 Hz), 2.00 (3H, s).

Step 3

2-chloro-4-methyl-fluoren-9-one

Under anhydrous calcium chloride drying conditions, a mixture of 4′-chloro-2′-methyl-biphenyl-2-carboxylic acid (21.60 g) and Eaton's reagent (7.7 w/w % solution of phosphorus pentoxide in methanesulfonic acid) (170 ml) was stirred at 100° C. for 2.5 hr. The reaction mixture was ice-cooled, water (500 ml) was slowly added dropwise, and the mixture was further stirred at room temperature for 10 min. This suspension was filtered, the obtained solid was mixed with 30 v/v % aqueous ethanol solution (200 ml), and the slurry was stirred at room temperature for 10 min, and filtered. The obtained solid was air-dried and dried under reduced pressure at 80° C. to give the title compound (19.744 g, 99%).

¹H-NMR (CDCl₃) δ: 7.69-7.66 (1H, m), 7.60-7.57 (1H, m), 7.52-7.46 (2H, m), 7.32-7.27 (1H, m), 7.25-7.23 (1H, m), 2.56 (3H, s).

Step 4

2-chloro-4-methyl-9-trifluoromethyl-9H-fluoren-9-ol

Under anhydrous calcium chloride drying conditions, 2-chloro-4-methyl-fluoren-9-one (18.627 g), potassium carbonate (3.372 g) and dimethylformamide (100 ml) were mixed, trimethyl(trifluoromethyl)silane (16 ml) was added dropwise over 25 min at room temperature with stirring, and the mixture was further stirred at room temperature for 14 min. To this mixture, a 1M solution (122 ml) of tetrabutylammonium fluoride in tetrahydrofuran was added dropwise over 6 min. To the reaction mixture was added aqueous ammonium chloride (400 ml), and the mixture was extracted with ethyl acetate (200 ml). The organic layer was washed once with water (100 ml), once with saturated aqueous sodium hydrogen carbonate and 3 times with water, and concentrated under reduced pressure. The obtained residue was dissolved in methanol (200 ml), activated carbon (1.5 g) was added, and the mixture was stirred at room temperature for 10 min. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (24.689 g). The obtained residue was directly used for the next reaction without further purification.

¹H-NMR (CDCl₃) δ: 7.78-7.75 (1H, m), 7.74-7.70 (1H, m), 7.55-7.53 (1H, m), 7.52-7.47 (1H, m), 7.40-7.35 (1H, m), 7.27-7.25 (1H, m), 2.80 (1H, brs), 2.64 (3H, s).

Step 5

2-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid

To a mixture of 2-chloro-4-methyl-9-trifluoromethyl-9H-fluoren-9-ol (2.987 g), pyridine (6 ml) and water (24 ml) was added potassium permanganate (7.902 g) at 100° C., and the mixture was stirred for 2 hr. To this mixture were added further potassium permanganate (4.70 g) and pyridine (6 ml) and the mixture was stirred at 100° C. for 2 hr. Potassium permanganate (4.70 g) was further added and the mixture was stirred at 100° C. for 2 hr. This operation was repeated twice. The reaction mixture was cooled to room temperature, and the insoluble material was filtered off and washed with water (50 ml). The filtrate was adjusted to pH 1 with 6N hydrochloric acid, and extracted with ethyl acetate (200 ml). The organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was treated with hexane/ethyl acetate mixed solution (hexane:ethyl acetate=9:1) (30 ml). This slurry was filtered, and the obtained solid was dried to give the title compound (2.509 g, 76%).

¹H-NMR (DMSO-D₆) δ: 13.91 (1H, br s), 8.22-8.19 (1H, m), 7.87 (1H, d, J=2.0 Hz), 7.81-7.79 (1H, m), 7.72-7.68 (1H, m), 7.57-7.51 (2H, m), 7.51-7.46 (1H, m).

Step 6

salt of optically active form of 2-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid and (S)-(−)-1-phenylethylamine

Step 6-1 Synthesis of Seed Crystal

To a solution of 2-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid (0.100 g) in ethyl acetate (0.50 ml) was added (S)-(−)-1-phenylethylamine (0.040 ml), and the mixture was stirred at room temperature for 2 days. This suspension was filtered, and the obtained solid was dried under reduced pressure to give the title compound (0.062 g, containing 8 w/w % ethyl acetate, 41%). The solid was analyzed under HPLC analysis condition 2 to find that the isomer with a short retention time was the main component.

isomer with short retention time (retention time 20.35 min) isomer with long retention time (retention time 21.10 min)

¹H-NMR (DMSO-D₆) δ: 8.38 (1H, d, J=7.2 Hz), 8.29 (3H, br s), 7.61-7.57 (1H, m), 7.51-7.48 (2H, m), 7.45-7.32 (7H, m), 7.30 (1H, br s), 4.38 (1H, q, J=6.8 Hz), 1.49 (3H, d, J=6.7 Hz).

Step 6-2

To a solution of 2-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid (0.972 g) in ethyl acetate (5.0 ml) were added (S)-(−)-1-phenylethylamine (0.38 ml) and a seed crystal of a salt of an optically active form of 2-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid and (S)-(−)-1-phenylethylamine, and the mixture was stirred at room temperature for 2 days. This suspension was filtered, and the obtained solid was dried under reduced pressure to give the title compound (0.608 g, containing 16 w/w % ethyl acetate, 38%). The solid was analyzed under HPLC analysis condition 2 to find that the isomer with a short retention time was the main component.

isomer with short retention time (retention time 20.31 min) isomer with long retention time (retention time 21.06 min)

¹H-NMR (DMSO-D₆) δ: 8.38 (1H, d, J=7.1 Hz), 8.34 (3H, br s), 7.61-7.57 (1H, m), 7.51-7.48 (2H, m), 7.46-7.32 (7H, m), 7.30 (1H, br s), 4.38 (1H, q, J=6.8 Hz), 1.50 (3H, d, J=6.8 Hz).

Step 7

optically active form of 2-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid

A salt of an optically active form of 2-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid and (S)-(−)-1-phenylethylamine (0.575 g) was dissolved in ethyl acetate, and the mixture was placed in a separatory funnel, hydrochloric acid was added, and the mixture was partitioned. The organic layer was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (0.357 g).

¹H-NMR (DMSO-D₆) δ: 13.90 (1H, br s), 8.22-8.19 (1H, m), 7.87 (1H, d, J=2.0 Hz), 7.81-7.79 (1H, m), 7.72-7.68 (1H, m), 7.57-7.46 (3H, m).

Step 8

1-ethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole

4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (5.0 g), N,N-dimethylacetamide (50 ml), potassium carbonate (5.3 g) and ethyl iodide (2.1 ml) were mixed, and the mixture was stirred at 60° C. overnight. The reaction mixture was cooled to room temperature, water (100 ml) and ethyl ether (100 ml) were added, and the mixture was partitioned in a separatory funnel. The aqueous layer was further extracted with ethyl ether (100 ml), and the organic layers were combined. The organic layer was washed 3 times with water (100 ml) and once with saturated brine (100 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, hexane (50 ml) was added to the obtained residue and the mixture was partitioned in a separatory funnel. The organic layer was washed 3 times with water (40 ml) and once with saturated brine (40 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (2.1691 g, 38%).

¹H-NMR (CDCl₃) δ: 7.79 (1H, s), 7.70 (1H, s), 4.19 (2H, q, J=7.3 Hz), 1.49 (3H, t, J=7.3 Hz), 1.32 (12H, s).

Step 9

optically active form of 2-(1-ethyl-1H-pyrazol-4-yl)-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid

Under an argon atmosphere, an optically active form (0.100 g) of 2-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid, 1-ethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.133 g), tripotassium phosphate (0.191 g), palladium(II) acetate (0.0034 g), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.0123 g), dioxane (3 ml) and water (0.6 ml) were mixed, and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was cooled to room temperature, hydrochloric acid and ethyl acetate were added, and the mixture was partitioned in a separatory funnel. The organic layer was washed twice with water and once with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was treated with hexane/ethyl acetate mixed solution (hexane:ethyl acetate-1:2.2 ml). This slurry was filtered, and the obtained solid was dried to give the title compound (0.075 g, 63%).

¹H-NMR (DMSO-D₆) δ: 13.60 (1H, s), 8.43 (1H, s), 8.18-8.15 (1H, m), 8.01 (1H, d, J=0.7 Hz), 8.00 (1H, d, J=1.6 Hz), 7.97-7.95 (1H, m), 7.70-7.66 (1H, m), 7.53-7.48 (1H, m), 7.45-7.40 (1H, m), 7.35 (1H, s), 4.17 (2H, q, J=7.3 Hz), 1.43 (3H, t, J=7.3 Hz).

Step 10

(−)-2-(1-ethyl-1H-pyrazol-4-yl)-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxamide

To a mixture of an optically active form (0.051 g) of 2-(1-ethyl-1H-pyrazol-4-yl)-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.038 g), 1-hydroxybenzotriazole hydrate (0.030 g), ammonium chloride (0.022 g) and dimethylformamide (1 ml) was added triethylamine (0.055 ml), and the mixture was stirred at room temperature overnight. To the reaction mixture was added ethyl acetate (10 ml), and the organic layer was successively washed once with hydrochloric acid, once with water, twice with saturated aqueous sodium hydrogen carbonate, 3 times with water and once with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (0.043 g, 85%).

[α]D=−3.00° (20° C., c=0.20, methanol)

¹H-NMR (DMSO-D₆) δ: 8.37 (1H, s), 8.14 (1H, br s), 7.98 (1H, J=0.7 Hz), 7.93-7.90 (1H, m), 7.85-7.83 (1H, m), 7.74 (1H, br s), 7.70 (1H, d, J=1.5 Hz), 7.67-7.64 (1H, m), 7.49-7.44 (1H, m), 7.40-7.35 (1H, m), 7.30 (1H, s), 4.17 (2H, q, J=7.3 Hz), 1.42 (3H, t, J=7.3 Hz).

Using the above-mentioned optically active form of 2-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-4-carboxylic acid as an intermediate and by a similar method, compound Nos. 629, 659, 660, 667 and 668 were synthesized.

Example 6 Synthesis of (−)-1-(9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carbonyl)-azetidine-3-carboxylic acid dimethylamide (compound No. 153) Step 1

2-ethyl 4′-methyl 2′-methyl-biphenyl-2,4′-dicarboxylate

Under a nitrogen atmosphere, to a mixture of methyl 4-bromo-3-methylbenzoate (2.291 g), ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (3.313 g), toluene (20 ml), water (10 ml) and tripotassium phosphate (4.246 g) was added tetrakis(triphenylphosphine)palladium(0) (0.578 g) at room temperature, and the mixture was stirred with heating under reflux overnight. The reaction mixture was cooled to room temperature, and partitioned in a separatory funnel. The organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=95/5) to give the title compound (2.404 g, 81%)

¹H-NMR (CDCl₃) δ: 8.03-7.99 (1H, m), 7.94-7.91 (1H, m), 7.89-7.85 (1H, m), 7.59-7.53 (1H, m), 7.49-7.43 (1H, m), 7.21-7.18 (1H, m), 7.17-7.14 (1H, m), 4.07-4.01 (2H, m), 3.93 (3H, s), 2.11 (3H, s), 0.98-0.93 (3H, m).

Step 2

2′-methyl-biphenyl-2,4′-dicarboxylic acid

A mixture of 2-ethyl 4′-methyl 2′-methyl-biphenyl-2,4′-dicarboxylate (2.404 g), ethanol (12 ml) and 4N aqueous sodium hydroxide solution (6 ml) was stirred at 100° C. overnight. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and water (50 ml) was added to the obtained residue. This mixture was adjusted to pH 1 with 6N hydrochloric acid (5 ml), ethanol (10 ml) was added, and the mixture was stirred at room temperature for 10 min. This suspension was filtered, the obtained solid was washed with 20 v/v % ethanol-water (10 ml), air-dried, and dried under reduced pressure at 80° C. to give the title compound (1.957 g, 95%).

¹H-NMR (DMSO-D₆) δ: 12.74 (2H, br s), 7.92 (1H, dd, J=7.8, 1.3 Hz), 7.82-7.80 (1H, m), 7.76 (1H, dd, J=7.9, 1.6 Hz), 7.65-7.60 (1H, m), 7.54-7.49 (1H, m), 7.22 (1H, dd, J=7.7, 1.2 Hz), 7.15 (1H, d, J=7.9 Hz), 2.06 (3H, s).

Step 3

4-methyl-9-oxo-9H-fluorene-2-carboxylic acid

A mixture of 2′-methyl-biphenyl-2,4′-dicarboxylic acid (1.94 g) and polyphosphoric acid (50 g) was stirred at 180° C. for 3 hr. The reaction mixture was cooled to room temperature, water (100 ml) was slowly added dropwise, and the mixture was further stirred at room temperature for 10 min. This suspension was filtered, and the obtained solid was successively washed with water (50 ml) and 50 v/v % aqueous methanol solution (50 ml). The obtained solid was air-dried, and dried under reduced pressure at 80° C. to give the title compound (1.745 g, 97%).

¹H-NMR (DMSO-D₆) δ: 12.98 (1H, br s), 8.00-7.99 (1H, m), 7.88 (1H, d, J=1.6 Hz), 7.86 (1H, d, J=7.4 Hz), 7.71-7.66 (2H, m), 7.49-7.45 (1H, m), 2.65 (3H, s).

Step 4

methyl 4-methyl-9-oxo-9H-fluorene-2-carboxylate

Under anhydrous calcium chloride drying conditions, 4-methyl-9-oxo-9H-fluorene-2-carboxylic acid (1.745 g), potassium carbonate (3.03 g) and dimethylformamide (20 ml) were mixed. To this mixture was added methyl iodide (0.92 ml) at room temperature, and the mixture was stirred for 3 hr 15 min. To the reaction mixture was added water (60 ml), and the mixture was stirred at room temperature for 30 min. The mixture was filtered and the obtained solid was air-dried and dried under reduced pressure at 80° C. to give the title compound (1.778 g, 96%).

¹H-NMR (CDCl₃) δ: 8.17 (1H, s), 8.01 (1H, s), 7.76-7.70 (2H, m), 7.58-7.52 (1H, m), 7.40-7.35 (1H, m), 3.94 (3H, s), 2.67 (3H, s).

Step 5

methyl 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylate

Under an argon atmosphere, methyl 4-methyl-9-oxo-9H-fluorene-2-carboxylate (1.009 g), trimethyl(trifluoromethyl)silane (0.89 ml) and dimethylformamide (50 ml) were mixed, lithium acetate (0.027 g) was added with stirring at room temperature, and the mixture was further stirred at room temperature for 30 min. Acetic acid (0.7 ml) and a 1M solution (6 ml) of tetrabutylammonium fluoride in tetrahydrofuran were added, and the mixture was further stirred at room temperature for 15 min. To the reaction mixture was added aqueous sodium hydrogen carbonate (300 ml), and the mixture was extracted twice with ethyl acetate (50 ml). The combined organic layer was washed once with saturated aqueous sodium hydrogen carbonate, 4 times with water and once with saturated brine, and concentrated under reduced pressure. To the obtained residue was added hexane/ethyl acetate (8:2, 10 ml) and the mixture was stirred for 10 min. This slurry was filtered, and the obtained solid was dried to give the title compound (1.000 g, 78%).

¹H-NMR (CDCl₃) δ: 8.20-8.19 (1H, m), 7.98-7.96 (1H, m), 7.86 (1H, d, J=7.7 Hz), 7.79-7.75 (1H, m), 7.56-7.51 (1H, m), 7.46-7.40 (1H, m), 3.93 (3H, s), 2.84 (1H, s), 2.71 (3H, s).

Step 6

9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid

A mixture of methyl 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylate (1.000 g), tetrahydrofuran (4 ml), methanol (6 ml) and 4N aqueous sodium hydroxide solution (1.6 ml) was stirred with heating under reflux for 3 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. Water (30 ml) was added to the obtained residue, and the mixture was adjusted to pH 1 with 6N hydrochloric acid (2 ml), and extracted with ethyl acetate (30 ml). The organic layer was successively washed with water and saturated brine. After addition of anhydrous magnesium sulfate and activated carbon (0.2 g), the mixture was stirred at room temperature for 10 min. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (1.053 g). The residue was directly used for the next reaction without further purification.

¹H-NMR (DMSO-D₆) δ: 13.07 (1H, br s), 8.06-8.03 (1H, m), 7.97-7.91 (2H, m), 7.74-7.71 (1H, m), 7.61-7.56 (1H, m), 7.51-7.46 (1H, m), 7.33 (1H, s), 2.70 (3H, s).

Step 7

salt of racemic 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and (R)-(+)-1-phenylethylamine

A mixture of 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid (0.159 g), (R)-(+)-1-phenylethylamine (0.066 ml), and ethyl acetate (2 ml) was concentrated under reduced pressure, ethyl acetate was added to the residue and the mixture was concentrated under reduced pressure again to give the title compound (0.229 g).

Step 8

salt of optically active form (enantiomer with long retention time under HPLC analysis condition 3) of 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and (R)-(+)-1-phenylethylamine

Salt (0.010 g) of the racemic 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and (R)-(+)-1-phenylethylamine obtained in Step 7 was dissolved in ethyl acetate (0.2 ml) and the mixture was stood at room temperature overnight. The obtained solid was collected by filtration, and dried under reduced pressure to give the title compound (0.0017 g). The solid was analyzed under HPLC analysis condition 3 to find that an isomer with a long retention time was the main component.

isomer with short retention time (retention time 23.27 min) isomer with long retention time (retention time 25.39 min)

Step 9

salt of optically active form (enantiomer with short retention time under HPLC analysis condition 3) of 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and (S)-(−)-1-phenylethylamine

Step 9-1 Synthesis of Seed Crystal

To a mixture of a salt (0.141 g) of the racemic 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and (R)-(+)-1-phenylethylamine obtained in Step 7 and ethyl acetate (0.70 ml) was added a salt of an optically active form (enantiomer with long retention time under HPLC analysis condition 3) of 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and (R)-(+)-1-phenylethylamine obtained in Step 8 as a seed crystal, and the mixture was stirred at room temperature for 30 min. Ethyl acetate (0.7 ml) was added to the mixture, and the mixture was further stirred at room temperature for 2 hr. This suspension was filtered, and the obtained solid was washed with ethyl acetate (4 ml). The filtrate was successively washed with 1N hydrochloric acid and water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue (0.046 g). The residue was dissolved in ethyl acetate (0.50 ml), (S)-(−)-1-phenylethylamine (0.019 ml) was added, and the mixture was stirred at room temperature overnight. This suspension was filtered, and the obtained solid was washed with ethyl acetate (2 ml), and dried. The solid was further mixed with ethyl acetate (0.5 ml), and the mixture was stirred at 70° C. for 30 min, and further at room temperature for 2 hr. This suspension was filtered, and the obtained solid was washed with ethyl acetate (2 ml), and dried to give the title compound (0.0357 g). The solid was analyzed under HPLC analysis condition 3 to find that an isomer with a short retention time was the main component.

isomer with short retention time (retention time 23.57 min) isomer with long retention time (retention time 25.65 min)

Step 9-2

To a solution of 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid (1.053 g) in ethyl acetate (15 ml) were added at 50° C. (S)-(−)-1-phenylethylamine (0.200 ml) and a seed crystal of a salt of an optically active form (enantiomer with short retention time under HPLC analysis condition 3) of 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and (S)-(−)-1-phenylethylamine obtained in Step 9-1, and the mixture was stirred at 50° C. for 5 min and at room temperature for 4 hr. This suspension was filtered, and the obtained solid was dried under reduced pressure to give the title compound (0.400 g). The solid was analyzed under HPLC analysis condition 3 to find that an isomer with a short retention time was the main component.

isomer with short retention time (retention time 23.49 min) isomer with long retention time (retention time 25.52 min)

Step 10

optically active form of 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid

Salt (0.390 g) of an optically active form (enantiomer with short retention time under HPLC analysis condition 3) of 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and (S)-(−)-1-phenylethylamine was mixed with ethyl acetate (10 ml), hydrochloric acid was added, and the mixture was partitioned. The organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (0.310 g).

¹H-NMR (DMSO-D₆) δ: 13.10 (1H, br s), 8.06-8.03 (1H, m), 7.97-7.91 (2H, m), 7.75-7.71 (1H, m), 7.61-7.56 (1H, m), 7.51-7.46 (1H, m), 7.35 (1H, s), 2.70 (3H, s).

Step 11

t-butyl 3-dimethylcarbamoyl-azetidine-1-carboxylate

Under a nitrogen atmosphere, triethylamine (1.2 ml) was added to a mixture of 1-(t-butyloxycarbonyl)-azetidine-3-carboxylic acid (0.804 g), dimethylamine hydrochloride (0.489 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.997 g), 1-hydroxybenzotriazole hydrate (0.796 g), and dimethylformamide (8 ml), and the mixture was stirred at room temperature for 3 days. To the reaction mixture was added ethyl acetate (30 ml), and the mixture was successively washed once with water, once with hydrochloric acid, once with water, twice with saturated aqueous sodium hydrogen carbonate and twice with water. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (0.364 g, 40%).

¹H-NMR (CDCl₃) δ: 4.17 (2H, br s), 4.05 (2H, t, J=8.5 Hz), 3.52-3.43 (1H, m), 2.97 (3H, s), 2.88 (3H, s), 1.43 (9H, s).

Step 12

azetidine-3-carboxylic acid dimethylamide hydrochloride

A mixture of t-butyl 3-dimethylcarbamoyl-azetidine-1-carboxylate (0.365 g) and 4N hydrogen chloride/dioxane solution (5 ml) was stirred at room temperature for 5 hr 15 min. The reaction mixture was concentrated under reduced pressure, dioxane was added to the obtained residue and the mixture was concentrated again under reduced pressure. The obtained residue was dried under reduced pressure at 60° C. to give the title compound (0.290 g). The obtained residue was directly used for the next reaction without further purification.

¹H-NMR (DMSO-D₆) δ: 9.38 (1H, br s), 8.95 (1H, br s), 4.10-3.99 (4H, m), 3.94-3.85 (1H, m), 2.85 (3H, s), 2.82 (3H, s).

Step 13

(−)-1-(9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carbonyl)-azetidine-3-carboxylic acid dimethylamide

To a mixture of an optically active form (0.080 g) of 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid, azetidine-3-carboxylic acid dimethylamide hydrochloride (0.060 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.065 g), 1-hydroxybenzotriazole hydrate (0.052 g) and dimethylformamide (2 ml) was added triethylamine (0.073 ml), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added ethyl acetate (15 ml), and the mixture was successively washed once with hydrochloric acid, once with water, twice with saturated aqueous sodium hydrogen carbonate and 3 times with water. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was treated with ethyl ether. This slurry was filtered and the obtained solid was dried to give the title compound (0.054 g, 50%).

[α]D=−12.53° (25° C., c=0.744, methanol)

¹H-NMR (CDCl₃) δ: 7.85-7.74 (3H, m), 7.54-7.48 (1H, m), 7.45-7.38 (2H, m), 4.74-4.64 (1H, m), 4.43-4.32 (2H, m), 4.25-4.11 (1H, m), 3.94-3.86 (1H, m), 3.65-3.54 (1H, m), 2.98 (3H, s), 2.91 (3H, s), 2.64 (3H, s).

Using the above-mentioned optically active form of 9-hydroxy-4-methyl-9-trifluoromethyl-9H-fluorene-2-carboxylic acid as an intermediate and by a similar method, compound Nos. 136 and 152 were synthesized.

Example 7 Synthesis of 1-[2-(5-hydroxy-5-trifluoromethyl-5-H-indeno[1,2-b]pyridin-3-yloxy)-ethyl]-pyrrolidin-2-one (compound No. 430) Step 1

2-chloro-5-methoxy-pyridine

Under a nitrogen atmosphere, potassium carbonate (5.52 g) was added to a mixture of 2-chloro-5-hydroxy-pyridine (2.591 g), methyl iodide (1.50 ml) and dimethylformamide (26 ml), and the mixture was stirred at room temperature for 18 hr. To the reaction mixture was added ethyl acetate and the mixture was placed in a separatory funnel. The organic layer was washed 4 times with aqueous ammonium chloride, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (2.403 g, 84%).

¹H-NMR (CDCl₃) δ: 8.07 (1H, d, J=3.0 Hz), 7.24 (1H, dd, J=8.8, 0.7 Hz), 7.20 (1H, dd, J=8.6, 3.0 Hz), 3.87 (3H, s).

Step 2

2-(5-methoxy-pyridin-2-yl)-benzoic acid diethylamide

Under an argon atmosphere, a mixture of tripotassium phosphate (6.24 g) and water (15 ml) was added to a mixture of 2-chloro-5-methoxy-pyridine (2.05 g), 2-(diethylcarbamoyl)benzeneboronic acid (4.65 g), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (0.584 g) and toluene (30 ml), and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was cooled to room temperature, water (20 ml), citric acid (2.2 g) and ethyl acetate were added and the mixture was stirred and filtered through celite. The filtrate was partitioned in a separatory funnel. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1 to 1/2) to give a roughly purified product (1.144 g) of the title compound. This product was directly used for the next reaction without further purification.

¹H-NMR (CDCl₃) δ: 8.33 (1H, d, J=2.9 Hz), 7.68 (1H, dd, J=7.7, 1.3 Hz), 7.60 (1H, d, J=8.6 Hz), 7.48-7.32 (3H, m), 7.25-7.15 (1H, m), 3.88 (3H, s), 3.32-2.78 (4H, m), 1.07 (3H, t, J=7.1 Hz), 0.81 (3H, t, J=7.2 Hz).

Step 3

3-methoxy-indeno[1,2-b]pyridin-5-one

Under an argon atmosphere, a 2.66M solution (1.96 ml) of n-butyllithium in n-hexane was added to a solution of N,N-diisopropylamine (0.734 ml) in tetrahydrofuran (20 ml) at 0° C., and the mixture was stirred at 0° C. for 30 min. To this mixture was added a solution (10 ml) of 2-(5-methoxy-pyridin-2-yl)-benzoic acid diethylamide (1.14 g) in tetrahydrofuran at 0° C. and the mixture was stirred at 0° C. for 30 min, and further at room temperature for 1 hr. To the reaction mixture was added aqueous ammonium chloride solution and the mixture was placed in a separatory funnel, and separated into layers by adding ethyl acetate. The organic layer was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was treated with ethyl ether at room temperature for 1 hr. This slurry was filtered, and the obtained solid was dried to give the title compound (0.183 g, 22%). The filtrate was concentrated under reduced pressure and the obtained residue was treated with ethyl ether at room temperature for 20 min. This slurry was filtered, and the obtained solid was dried to further give the title compound (0.128 g, 15%). The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1) to further give the title compound (0.134 g, 16%).

¹H-NMR (DMSO-D₆) δ: 8.37 (1H, d, J=2.8 Hz), 7.73-7.64 (3H, m), 7.60 (1H, d, J=3.0 Hz), 7.46-7.42 (1H, m), 3.91 (3H, s).

Step 4

3-hydroxy-indeno[1,2-b]pyridin-5-one [

118]

Under an argon atmosphere, 3-methoxy-indeno[1,2-b]pyridin-5-one (0.545 g) and pyridinium chloride (5.89 g) were mixed with pyridine (1.0 ml). The reaction mixture was stirred with heating at 180° C. for 30 min while evaporating pyridine, and further stirred with heating at 200° C. for 4 hr. The mixture was cooled to room temperature, water was added and the mixture was stirred for 30 min. This slurry was filtered, and the obtained solid was dried under reduced pressure to give the title compound (0.054 g). The obtained solid was used for the next reaction without further purification.

¹H-NMR (DMSO-D₆) δ: 10.53 (1H, br s), 8.19 (1H, d, J=2.8 Hz), 7.68-7.61 (3H, m), 7.43-7.38 (1H, m), 7.29 (1H, d, J=2.6 Hz).

Step 5

3-[2-(2-oxo-pyrrolidin-1-yl)-ethoxy]-indeno[1,2-b]pyridin-5-one

3-Hydroxy-indeno[1,2-b]pyridin-5-one (0.0500 g), di-t-butyl azodicarboxylate (0.087 g) and triphenylphosphine (0.10 g) were mixed with tetrahydrofuran (1.0 ml), 1-(2-hydroxy-ethyl)-2-pyrrolidone (0.043 ml) was added thereto, and the mixture was stirred at room temperature for 1 day. The mixture was purified by preparative thin layer chromatography (silica gel, eluent: ethyl acetate/methanol=10/1) to give the title compound (0.0386 g, 49%).

¹H-NMR (DMSO-D₆) δ: 8.36 (1H, d, J=2.8 Hz), 7.73-7.64 (3H, m), 7.63 (1H, d, J=2.8 Hz), 7.47-7.42 (1H, m), 4.27 (2H, t, J=5.4 Hz), 3.57 (2H, t, J=5.4 Hz), 3.49-3.44 (2H, m), 2.25-2.19 (2H, m), 1.97-1.87 (2H, m).

Step 6

1-[2-(5-hydroxy-5-trifluoromethyl-5-H-indeno[1,2-b]pyridin-3-yloxy)-ethyl]-pyrrolidin-2-one

3-[2-(2-Oxo-pyrrolidin-1-yl)-ethoxy]-indeno[1,2-b]pyridin-5-one (0.0376 g) and potassium carbonate (0.001 g) were mixed with dimethylformamide (1.0 ml), and the mixture was stirred at 0° C. To this mixture was added trimethyl(trifluoromethyl)silane (0.035 ml), and the mixture was stirred at 0° C. for 1 hr. Trimethyl(trifluoromethyl)silane (0.018 ml) was further added, and the mixture was stirred at 0° C. for 1 hr. To the reaction mixture was added acetic acid (0.010 ml), then a 1M solution (0.12 ml) of tetrabutylammonium fluoride in tetrahydrofuran was added, and the mixture was stirred at 0° C. for 30 min. To the reaction mixture was added ethyl acetate (20 ml), and the mixture was placed in a separatory funnel. The organic layer was washed 3 times with water (10 ml) and once with saturated brine (10 ml). The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (silica gel, eluent: n-hexane/ethyl acetate=7/3) to give the title compound (0.0389 g, 68%).

¹H-NMR (DMSO-D₆) δ: 8.36 (1H, d, J=2.8 Hz), 7.82-7.78 (1H, m), 7.71-7.66 (1H, m), 7.60-7.54 (2H, m), 7.50 (1H, s), 7.48-7.43 (1H, m), 4.25 (2H, t, J=5.4 Hz), 3.59 (2H, t, J=5.4 Hz), 3.51-3.45 (2H, m), 2.26-2.19 (2H, m), 1.97-1.88 (2H, m).

Example 8 Synthesis of optically active form of (4-bromo-9-hydroxy-9-trifluoromethyl-9H-fluoren-2-yloxy)-acetic acid methyl ester (compound No. 451) and the like Step 1

salt of optically active form of (4-bromo-9-hydroxy-9-trifluoromethyl-9H-fluoren-2-yloxy)-acetic acid and (S)-(−)-1-phenylethylamine

(4-Bromo-9-hydroxy-9-trifluoromethyl-9H-fluoren-2-yloxy)-acetic acid (0.176 g) and (S)-(−)-1-phenylethylamine (0.057 ml) were mixed with ethyl acetate (1 ml). The mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate, and the mixture was concentrated under reduced pressure to give a residue (0.233 g). Under a nitrogen atmosphere, the residue (0.160 g) and ethyl acetate (2.0 ml) were mixed. The mixture was stirred with heating at 80° C. until insoluble material was solved, and stirred at room temperature overnight. This suspension was filtered to give a solid (0.044 g). The solid was mixed with ethyl ether/ethyl acetate (1:1, 1 ml), and the mixture was stirred at room temperature for 1 hr. This suspension was filtered, and the obtained solid was washed with ethyl ether/ethyl acetate (1:1, 2 ml). The obtained solid was dried under reduced pressure to give the title compound (0.023 g). The solid was analyzed under HPLC analysis condition 2 to find that an isomer with a long retention time was the main component.

isomer with short retention time (retention time 16.50 min) isomer with long retention time (retention time 17.58 min)

Using the salt as an intermediate, compound Nos. 451, 467, 474, 475 and 477 were synthesized.

Example 9 Synthesis of optically active form of 4-[9-hydroxy-4-(1-methyl-1H-pyrazol-4-yl)-9-trifluoromethyl-9H-fluoren-2-yloxy]-butyric acid (compound No. 504) and the like Step 1

salt of optically active form of 4-(4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluoren-2-yloxy)-butyric acid and (S)-(−)-1-(4-methylphenyl)ethylamine

4-(4-Chloro-9-hydroxy-9-trifluoromethyl-9H-fluoren-2-yloxy)-butyric acid (0.100 g) and isopropyl ether (2.0 ml) were mixed, (S)-(−)-1-(4-methylphenyl)ethylamine (0.0189 ml) was added, and the mixture was stirred at room temperature for 17 hr. This suspension was filtered to give a salt (0.0403 g) of an optically active form of 4-(4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluoren-2-yloxy)-butyric acid and (S)-(−)-1-(4-methylphenyl)ethylamine. The solid was analyzed under HPLC analysis condition 2 to find that an isomer with a long retention time was the main component.

isomer with short retention time (retention time 19.97 min) isomer with long retention time (retention time 22.06 min)

Using this salt as an intermediate, compound Nos. 504, 553, 554, 561, 573, 577, 604, 624, 669, 676, 678, 679, 680, 681, 683, 684, 688, 689 and 698 were synthesized.

Example 10 Synthesis of optically active form of (4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluoren-2-yloxy)-acetic acid methyl ester (compound No. 481) and the like Step 1

salt of optically active form of (4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluoren-2-yloxy)-acetic acid and (S)-(−)-1-phenylethylamine

Under a nitrogen atmosphere, (S)-(−)-1-phenylethylamine (0.011 ml) was added to a mixture of (4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluoren-2-yloxy)-acetic acid (0.100 g) and isopropyl ether (5.0 ml), and the mixture was stirred at room temperature overnight. This suspension was filtered, and the obtained solid was dried under reduced pressure to give the title compound (0.0414 g). The solid was analyzed under HPLC analysis condition 2 to find that an isomer with a long retention time was the main component.

isomer with short retention time (retention time 15.67 min) isomer with long retention time (retention time 16.39 min)

Using this salt as an intermediate, compound Nos. 481, 540, 541, 542, 552, 581, 582, 588, 589, 614 and 619 were synthesized.

Example 11 Synthesis of optically active form of 4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-2-carboxylic acid methyl ester (compound No. 647) and the like

Salt of optically active form of 4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and (S)-(−)-1-phenylethylamine

Step 1-1 Synthesis of Seed Crystal

To a mixture of 4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-2-carboxylic acid (0.050 g) and isopropyl ether (0.250 ml) was added (S)-(−)-1-phenylethylamine (0.020 ml), and the mixture was stirred at room temperature overnight. This suspension was filtered to give a solid (0.060 g). The solid was added as a seed crystal to a mixture of 4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-2-carboxylic acid (0.050 g), (S)-(−)-1-phenylethylamine (0.020 ml) and ethyl acetate (0.250 ml), which had been stirred overnight at room temperature in advance, and the mixture was further stirred at room temperature overnight. The resulting suspension was filtered, and the obtained solid was washed with ethyl acetate. The solid was dried under reduced pressure to give the title compound (0.019 g). The solid was analyzed under HPLC analysis condition 4 to find that an isomer with a long retention time was the main component.

isomer with short retention time (retention time 20.09 min) isomer with long retention time (retention time 21.19 min)

Step 1-2

Under an argon atmosphere, (S)-(−)-1-phenylethylamine (0.392 ml) and a seed crystal of a salt of an optically active form of 4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-2-carboxylic acid and (S)-(−)-1-phenylethylamine were added to a mixture of 4-chloro-9-hydroxy-9-trifluoromethyl-9H-fluorene-2-carboxylic acid (1.000 g) and ethyl acetate (5 ml), and the mixture was stirred at room temperature for 3 days. This suspension was filtered, and the obtained solid was washed with ethyl acetate (3 ml). The solid was dried under reduced pressure to give the title compound (0.466 g). The solid was analyzed under HPLC analysis condition 4 to find that an isomer with a long retention time was the main component.

isomer with short retention time (retention time 19.91 min) isomer with long retention time (retention time 21.00 min)

Using this salt as an intermediate, compound Nos. 647, 657, 664 and 665 were synthesized.

Example 12 Synthesis of (+)-2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-2-hydroxymethyl-propane-1,3-diol (compound No. 703) Step 1

optically active form of 2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-3-hydroxy-2-hydroxymethyl-propionic acid

To a solution of an optically active form (33.3 g) of t-butyl [4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-acetate and paraformaldehyde (18.3 g) in dimethylformamide (100 ml) was added at room temperature a 1M solution (244 ml) of tetrabutylammonium fluoride in tetrahydrofuran, and the mixture was stirred at 90° C. for 4 hr. To the reaction mixture was added 1N hydrochloric acid (400 ml), m and the mixture was extracted with ethyl acetate (200 ml). The separated aqueous layer was extracted twice with ethyl acetate (100 ml). The combined organic layer was successively washed once with 1N hydrochloric acid (100 ml), twice with brine (water/saturated brine=100 ml/10 ml) and once with saturated brine (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was azeotroped twice with toluene to give the title compound (28.3 g).

¹H-NMR (DMSO-D₆) δ: 13.13 (1H, br s), 8.12 (1H, d, J=0.7 Hz), 7.73 (1H, d, J=0.5 Hz), 7.66-7.61 (1H, m), 7.48-7.45 (1H, m), 7.42-7.38 (2H, m), 7.36-7.31 (1H, m), 7.28-7.19 (2H, m), 5.15 (2H, br s), 4.24-4.07 (4H, m).

Step 2

(+)-2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-2-hydroxymethyl-propane-1,3-diol

To a solution of an optically active form (28.3 g) of 2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-3-hydroxy-2-hydroxymethyl-propionic acid in tetrahydrofuran (40 ml) were successively added dropwise at room temperature a 0.93M solution (225 ml) of borane-tetrahydrofuran complex in tetrahydrofuran and a 1.09M solution (32 ml) of borane-tetrahydrofuran complex in tetrahydrofuran, and the mixture was stirred for 3 hr. To the reaction mixture, ethanol (57 ml) was added dropwise at room temperature and the mixture was stirred at 80° C. for 1 hr. To this mixture were added water (150 ml) and saturated aqueous sodium hydrogen carbonate (100 ml), and the mixture was extracted twice with ethyl acetate (100 ml, 50 ml). The combined organic layer was successively washed twice with water (100 ml) and once with saturated brine (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. A solution of the obtained residue in ethanol (50 ml) was cooled to 0° C., sodium borohydride (2.3 g) was added thereto, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 1N hydrochloric acid (100 ml), and the mixture was extracted with ethyl acetate (100 ml). The separated aqueous layer was extracted again with ethyl acetate (50 ml). The combined organic layer was successively washed with water (100 ml), saturated aqueous sodium hydrogen carbonate (100 ml) and saturated brine (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1 to 9/1) to give the title compound (21.6 g).

[α]D=+71.5° (25° C., c=1.000, methanol)

¹H-NMR (DMSO-D₆) δ: 8.05 (1H, d, J=0.7 Hz), 7.70 (1H, d, J=0.7 Hz), 7.65-7.61 (1H, m), 7.51-7.47 (1H, m), 7.40-7.36 (2H, m), 7.35-7.30 (1H, m), 7.29-7.24 (1H, m), 7.21-7.17 (1H, m), 4.83 (3H, t, J=5.4 Hz), 3.90 (6H, d, J=5.6 Hz).

Example 13 Synthesis of (+)-2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-2-methyl-propane-1,3-diol (compound No. 673) Step 1

2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propionic acid ethyl ester

To a suspension of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (21.3 g) and potassium carbonate (20.7 g) in dimethylformamide (100 ml) was added 2-bromo-propionic acid ethyl ester (13 ml) and the mixture was stirred at 80° C. for 14 hr. The reaction mixture was cooled to 0° C., and toluene (100 ml) and water (150 ml) were successively added dropwise. The mixture was partitioned, and the aqueous layer was extracted with toluene (50 ml). The combined organic layer was successively washed once with 10% aqueous potassium carbonate (50 ml), twice with water (50 ml) and once with saturated brine (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (21.6 g).

¹H-NMR (CDCl₃) δ: 7.85 (1H, s), 7.81 (1H, s), 5.10 (1H, q, J=7.3 Hz), 4.19 (2H, q, J=7.1 Hz), 1.78 (3H, d, J=7.4 Hz), 1.32 (12H, s), 1.25 (3H, t, J=7.2 Hz).

Step 2

optically active form of 2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionic acid ethyl ester

To a suspension of 2-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-propionic acid ethyl ester (29.2 g), (+)-4-chloro-2-fluoro-9-trifluoromethyl-9H-fluoren-9-ol (20.4 g), and sodium hydrogen carbonate (11.1 g) in toluene/water (200 ml/66 ml) were added palladium acetate (743 mg) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (2.72 g) at room temperature, and the mixture was stirred at 115° C. for 8 hr. To the reaction mixture were added activated carbon (10 g) and Celite (10 g) at room temperature and the mixture was stirred for 1 hr. The mixture was filtered through celite, and the solid was washed with toluene (100 ml). The filtrate was partitioned, and the aqueous layer was extracted with toluene (60 ml). The combined organic layer was washed 3 times with water (100 ml), and once with saturated brine (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a solution of the obtained residue in toluene/ethyl acetate (3/1, 130 ml) was added silica gel (40 g), and the mixture was stirred at room temperature for 1 hr. The mixture was filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1 to 2/1) to give the title compound (27.9 g).

¹H-NMR (DMSO-D₆) δ: 8.20-8.18 (1H, m), 7.72-7.71 (1H, m), 7.67-7.63 (1H, m), 7.44-7.40 (2H, m), 7.37-7.23 (4H, m), 5.40-5.34 (1H, m), 4.22-4.15 (2H, m), 1.78-1.75 (3H, m), 1.23-1.18 (3H, m).

Step 3

optically active form of 2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-3-hydroxy-2-methyl-propionic acid

To a solution of an optically active form (27.9 g) of 2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionic acid ethyl ester and paraformaldehyde (17.0 g) in dimethylformamide (100 ml) was added at room temperature a 1M solution (170 ml) of tetrabutylammonium fluoride in tetrahydrofuran, and the mixture was stirred at 100° C. for 6 hr. The reaction mixture was filtered through celite, and the solid was washed with ethyl acetate (100 ml). To the filtrate was added 1N hydrochloric acid (400 ml), and the mixture was extracted with ethyl acetate (100 ml). The separated aqueous layer was extracted twice with ethyl acetate (100 ml). The combined organic layer was successively washed once with 1N hydrochloric acid (100 ml), twice with brine (water/saturated brine=100 ml/10 ml) and once with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was azeotroped twice with toluene to give the title compound (26.6 g).

¹H-NMR (DMSO-D₆) δ: 8.19-8.17 (1H, m), 7.71-7.70 (1H, m), 7.66-7.61 (1H, m), 7.46-7.19 (7H, m), 5.35-5.22 (1H, m), 4.21-4.12 (1H, m), 3.96-3.88 (1H, m), 1.80 (3H, s).

Step 4

(+)-2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-2-methyl-propane-1,3-diol

To a solution of an optically active form (26.6 g) of 2-[4-(2-fluoro-9-hydroxy-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-3-hydroxy-2-methyl-propionic acid in tetrahydrofuran (40 ml) was added dropwise at room temperature a 1.09M solution (200 ml) of borane-tetrahydrofuran complex in tetrahydrofuran, and the mixture was stirred for 3 hr. To the reaction mixture was added dropwise ethanol (25 ml) at room temperature and the mixture was stirred at 80° C. for 1 hr. To this mixture were added water (200 ml) and saturated aqueous sodium hydrogen carbonate (100 ml) and the mixture was extracted twice with ethyl acetate (100 ml). The combined organic layer was successively washed twice with water (100 ml) and once with saturated brine (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1 to 10/1) to give the title compound (17.4 g).

[α]D=+72.4° (25° C., c=1.004, methanol)

¹H-NMR (DMSO-D₆) δ: 8.05 (1H, d, J=0.7 Hz), 7.68 (1H, d, J=0.7 Hz), 7.65-7.62 (1H, m), 7.44-7.42 (1H, m), 7.40-7.36 (2H, m), 7.35-7.26 (2H, m), 7.21-7.17 (1H, m), 4.98-4.93 (2H, m), 3.84-3.79 (2H, m), 3.76-3.70 (2H, m), 1.52 (3H, s).

Example 14 Synthesis of (+)-2-hydroxymethyl-2-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propane-1,3-diol (compound No. 707) Step 1

optically active form of [4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-acetic acid t-butyl ester

To a suspension of t-butyl [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-acetate (24.8 g), (+)-4-chloro-2-methyl-9-trifluoromethyl-9H-fluoren-9-ol (20.0 g), and sodium hydrogen carbonate (11.3 g) in toluene/water (200 ml/60 ml) were added palladium acetate (750 mg) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (2.75 g) at room temperature and the mixture was stirred at 110° C. for 2 hr. To the reaction mixture were added water (80 ml) and activated carbon (2.0 g) at room temperature and the mixture was stirred for 1 hr. The mixture was filtered through celite, and the solid was washed with tetrahydrofuran (100 ml). The filtrate was partitioned and the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layer was successively washed twice with water (100 ml) and once with saturated brine (100 ml), anhydrous sodium sulfate and silica gel (40 g) were added, and the mixture was stirred overnight. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was treated with n-hexane/ethyl acetate (2/1, 120 ml) solution, and the resulting slurry was filtered to give the title compound (17.8 g).

¹H-NMR (CDCl₃) δ: 7.68-7.64 (1H, m), 7.65 (1H, d, J=0.7 Hz), 7.60 (1H, d, J=0.7 Hz), 7.51-7.49 (1H, m), 7.40-7.37 (1H, m), 7.28-7.23 (2H, m), 7.14-7.13 (1H, m), 4.93 (1H, d, J=17.4 Hz), 4.88 (1H, d, J=17.4 Hz), 4.80 (1H, s), 2.42 (3H, s), 1.52 (9H, s).

Step 2

optically active form of 3-hydroxy-2-hydroxymethyl-2-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionic acid

To a solution of an optically active form (17.8 g) of t-butyl [4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-acetate and paraformaldehyde (12.0 g) in dimethylformamide (60 ml) was added at room temperature a 1M solution (120 ml) of tetrabutylammonium fluoride in tetrahydrofuran, and the mixture was stirred at 95° C. for 3 hr. To the reaction mixture were added 1N hydrochloric acid (180 ml) and water (90 ml), and the mixture was extracted with ethyl acetate (180 ml). The separated aqueous layer was extracted twice with ethyl acetate (90 ml). The combined organic layer was successively washed once with 1N hydrochloric acid (90 ml), twice with water (90 ml) and once with saturated brine (90 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (15.5 g).

¹H-NMR (DMSO-D₆) δ: 13.10 (1H, br s), 8.03 (1H, s), 7.65 (1H, s), 7.63-7.59 (1H, m), 7.44-7.40 (2H, m), 7.31-7.27 (1H, m), 7.25-7.20 (1H, m), 7.15 (2H, s), 5.14 (2H, br s), 4.21-4.09 (4H, m), 2.39 (3H, s).

Step 3

(+)-2-hydroxymethyl-2-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propane-1,3-diol

To a solution of an optically active form (15.5 g) of 3-hydroxy-2-hydroxymethyl-2-[4-(9-hydroxy-2-methyl-9-trifluoromethyl-9H-fluoren-4-yl)-pyrazol-1-yl]-propionic acid in tetrahydrofuran (31 ml) was added dropwise at room temperature a 1.09M solution (127 ml) of borane-tetrahydrofuran complex in tetrahydrofuran, and the mixture was stirred for 5 hr. To the reaction mixture was added dropwise ethanol (15 ml) at room temperature and the mixture was stirred at 75° C. for 1 hr. To this mixture were added water (90 ml) and saturated aqueous sodium hydrogen carbonate (150 ml), and the mixture was extracted twice with ethyl acetate (150 ml, 75 ml). The combined organic layer was successively washed once with saturated aqueous sodium hydrogen carbonate (75 ml), twice with water (75 ml) and once with saturated brine (75 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. To a solution of the obtained residue in ethanol (45 ml) was added sodium borohydride (1.3 g) at room temperature, and the mixture was stirred for 1 hr. To the reaction mixture was added 1N hydrochloric acid (150 ml), and the mixture was extracted with ethyl acetate (150 ml). The separated aqueous layer was extracted again with ethyl acetate (75 ml). The combined organic layer was successively washed with water (75 ml), saturated aqueous sodium hydrogen carbonate (75 ml), water (75 ml) and saturated brine (75 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1 to 10/1) to give the title compound (12.6 g).

[α]D=+65.6° (25° C., c=1.008, methanol)

¹H-NMR (DMSO-D₆) δ: 7.96 (1H, d, J=0.7 Hz), 7.63-7.59 (1H, m), 7.62 (1H, d, J=0.7 Hz), 7.46-7.40 (2H, m), 7.31-7.21 (2H, m), 7.14 (2H, s), 4.82 (3H, t, J=5.6 Hz), 3.91 (6H, d, J=5.6 Hz), 2.39 (3H, s).

In the same manner as in the above-mentioned Examples, the compound Nos. 1 to 707 including the compounds shown in the above-mentioned Examples were obtained. The structural formulas and ¹H-NMR spectrum data of the obtained compounds are shown in Table 1-1 to Table 1-106.

In the Tables, optically active compounds are indicated with (optically active form) under compound No. Among them, those measured for optical rotation are marked with (+) or (−) in the structural formulas.

¹H-NMR spectrum was measured in CDCl₃ or DMSO-D₆ using tetramethylsilane as an internal standard, and all δ values are shown in ppm.

The symbols in the Tables mean the following.

s: singlet d: doublet t: triplet q: quartet dd: double doublet ddd: double double doublet brs: broad singlet m: multiplet J: coupling constant

TABLE 1-1 com- pound No. structural formula NMR 1

¹H-NMR (DMSO-D₆) δ: 8.65 (1H, dd, J = 5.1, 1.6 Hz), 8.04-8.01 (1H, m), 7.92-7.90 (1H, m), 7.75-7.72 (1H, m), 7.63- 7.59 (1H, m), 7.57-7.52 (1H, m), 7.50 (1H, s), 7.39 (1H, dd, J = 7.7, 4.9 Hz). 2

¹H-NMR (DMSO-D₆) δ: 7.85 (1H, d, J = 7.7 Hz), 7.70-7.66 (1H, m), 7.55- 7.49 (2H, m), 7.42-7.38 (1H, m), 7.32-7.27 (2H, m), 7.17 (1H, s), 2.64 (3H, s). 3

¹H-NMR (DMSO-D₆) δ: 7.79 (1H, d, J = 7.5 Hz), 7.73 (1H, d, J = 7.7 Hz), 7.63-7.59 (1H, m), 7.50- 7.44 (2H, m), 7.37-7.30 (2H, m), 7.17 (1H, s), 2.39 (3H, s). 4

¹H-NMR (DMSO-D₆) δ: 7.92 (1H, dd, J = 8.4, 5.1 Hz), 7.86 (1H, d, J = 7.5 Hz), 7.66-7.62 (1H, m), 7.54-7.49 (1H, m), 7.44-7.34 (4H, m). 5

¹H-NMR (CDCl₃) δ: 7.71-7.67 (2H, m), 7.65-7.63 (1H, m), 7.59 (1H, d, J = 7.9 Hz), 7.51-7.44 (2H, m), 7.40-7.36 (1H, m), 2.71 (1H, s). 6

¹H-NMR (CDCl₃) δ: 8.34 (1H, d, J = 7.7 Hz), 7.75-7.71 (1H, m), 7.65-7.61 (1H, m), 7.55- 7.51 (1H, m), 7.46-7.40 (2H, m), 7.32-7.27 (1H, m), 2.71 (1H, br s). 7

¹H-NMR (CDCl₃) δ: 7.86- 7.83 (1H, m), 7.72-7.61 (3H, m),m7.56-7.48 (2H, m), 7.43-7.38 (1H, m), 2.73 (1H, s).

TABLE 1-2 compound No. structural formula NMR  8

¹H-NMR (CDCl₃) δ: 7.74-7.71 (1H, m), 7.66-7.63 (1H, m), 7.60-7.57 (1H, m), 7.51-7.46 (1H, m), 7.43-7.37 (2H, m), 7.29-7.26 (1H, m), 3.73 (1H, s).  9

¹H-NMR (CDCl₃) δ: 7.72-7.68 (1H, m), 7.65-7.60 (3H, m), 7.52-7.47 (1H, m), 7.42-7.37 (1H, m), 7.33 (1H, dd, J = 8.1, 1.9 Hz), 2.69 (1H, s). 10

¹H-NMR (DMSO-D₆) δ: 7.81 (1H, d, J = 7.5 Hz), 7.68-7.66 (1H, m), 7.64-7.60 (1H, m), 7.53- 7.47 (2H, m), 7.39-7.35 (1H, m), 7.21-7.17 (1H, m), 7.15 (1H, s), 2.40 (3H, s). 11

¹H-NMR (DMSO-D₆) δ: 7.81-7.78 (1H, m), 7.71-7.68 (1H, m), 7.59-7.54 (1H, m), 7.53-7.50 (1H, m), 7.49-7.43 (2H, m), 7.44 (1H, s), 7.41-7.36 (1H, m). 12

¹H-NMR (DMSO-D₆) δ: 7.93-7.90 (1H, m), 7.79 (1H, dd, J = 9.0, 2.3 Hz), 7.67-7.63 (2H, m), 7.56-7.52 (1H, m), 7.45- 7.41 (1H, m), 7.31 (1H, s), 7.23-7.17 (1H, m). 13

¹H-NMR (DMSO-D₆) δ: 7.90 (1H, d, J = 7.4 Hz), 7.73 (1H, d, J = 7.7 Hz), 7.68-7.65 (1H, m), 7.60-7.52 (2H, m), 7.46- 7.41 (1H, m), 7.40 (1H, s), 7.21-7.15 (1H, m). 14

¹H-NMR (CDCl₃) δ: 7.67-7.65 (2H, m), 7.55 (2H, d, J = 8.1 Hz), 7.46 (2H, dd, J = 8.1, 2.1 Hz), 2.77 (1H, s).

TABLE 1-3 compound No. structural formula NMR 15

¹H-NMR (DMSO-D₆) δ: 8.67 (1H, dd, J = 5.1, 1.5 Hz), 8.03- 7.99 (1H, m), 7.57-7.53 (1H, m), 7.43-7.34 (4H, m), 2.80 (3H, s). 16

¹H-NMR (DMSO-D₆) δ: 8.61 (1H, dd, J = 5.1, 1.3 Hz), 7.98 (1H, d, J = 7.5 Hz), 7.78 (1H, d, J = 7.7 Hz), 7.56-7.53 (1H, m), 7.44-7.40 (2H, m), 7.35 (1H, dd, J = 7.6, 5.0 Hz), 2.43 (3H, s). 17

¹H-NMR (CDCl₃) δ: 7.67 (1H, d, J = 7.9 Hz), 7.56-7.53 (2H, m), 7.30-7.27 (1H, m), 7.24- 7.22 (2H, m), 2.66 (1H, br s), 2.64 (3H, s), 2.44 (3H, s). 18

¹H-NMR (CDCl₃) δ: 7.74 (1H, d, J = 7.7 Hz), 7.72-7.69 (1H, m), 7.49-7.44 (1H, m), 7.38- 7.36 (1H, m), 7.34-7.30 (1H, m), 7.08-7.06 (1H, m), 2.66 (1H, br s), 2.62 (3H, s), 2.39 (3H, s). 19

¹H-NMR (DMSO-D₆) δ: 9.95 (1H, br s), 7.77 (1H, d, J = 7.5 Hz), 7.67-7.62 (1H, m), 7.54- 7.48 (2H, m), 7.42-7.35 (3H, m), 7.26 (1H, s), 2.17 (3H, br s). 20

¹H-NMR (DMSO-D₆) δ: 7.89 (1H, d, J = 7.5 Hz), 7.64-7.60 (1H, m), 7.50-7.45 (1H, m), 7.35- 7.31 (1H, m), 7.21-7.17 (1H, m), 7.15-7.07 (1H, m), 7.05- 6.98 (1H, m), 6.13 (3H, br s). 21

¹H-NMR (DMSO-D₆) δ: 8.28-8.25 (1H, m), 7.80 (1H, d, J = 1.8 Hz), 7.74-7.71 (1H, m), 7.66- 7.64 (1H, m), 7.64-7.59 (1H, m), 7.61 (1H, s), 7.55-7.51 (1H, m).

TABLE 1-4 compound No. structural formula NMR 22

¹H-NMR (DMSO-D₆) δ: 10.14 (1H, br s), 7.97-7.96 (1H, m), 7.77-7.74 (2H, m), 7.71-7.68 (1H, m), 7.62-7.59 (1H, m), 7.49-7.45 (1H, m), 7.34-7.30 (1H, m), 7.22 (1H, s), 2.07 (3H, s). 23

¹H-NMR (DMSO-D₆) δ: 8.20-8.18 (1H, m), 8.14 (1H, dd, J = 8.0, 1.5 Hz), 8.03 (1H, d, J = 7.7 Hz), 8.00-7.97 (1H, m), 7.72-7.68 (1H, m), 7.60-7.56 (1H, m), 7.51-7.47 (1H, m), 7.48 (1H, s), 3.90 (3H, s). 24

¹H-NMR (DMSO-D₆) δ: 13.18 (1H, br s), 8.19-8.17 (1H, m), 8.11 (1H, dd, J = 8.0, 1.5 Hz), 8.00 (1H, d, J = 8.1 Hz), 7.98-7.95 (1H, m), 7.71-7.68 (1H, m), 7.59-7.55 (1H, m), 7.50-7.45 (1H, m), 7.43 (1H, s). 25

¹H-NMR (DMSO-D₆) δ: 7.83 (1H, d, J = 7.7 Hz), 7.70-7.66 (1H, m), 7.56-7.49 (2H, m), 7.42- 7.37 (1H, m), 7.33 (2H, d, J = 4.9 Hz), 7.16 (1H, s), 3.09- 2.95 (2H, m), 1.28 (3H, t, J = 7.5 Hz). 26

¹H-NMR (DMSO-D₆) δ: 7.62 (1H, d, J = 7.5 Hz), 7.57-7.54 (1H, m), 7.47-7.41 (1H, m), 7.34- 7.29 (1H, m), 7.28-7.24 (1H, m), 6.92 (1H, d, J = 2.0 Hz), 6.83 (1H, s), 6.53 (1H, dd, J = 8.3, 2.1 Hz), 5.44 (2H, br s). 27

¹H-NMR (DMSO-D₆) δ: 8.07-8.04 (1H, m), 7.88-7.82 (2H, m), 7.72-7.68 (1H, m), 7.55-7.44 (3H, m), 7.36 (1H, s), 3.97 (3H, s). 28

¹H-NMR (DMSO-D₆) δ: 10.17 (1H, br s), 8.06 (1H, d, J = 1.6 Hz), 7.73-7.70 (1H, m), 7.64- 7.61 (1H, m), 7.57-7.53 (1H, m), 7.53-7.47 (2H, m), 7.41- 7.37 (1H, m), 7.16 (1H, s), 2.09 (3H, 3).

TABLE 1-5 compound No. structural formula NMR 29

¹H-NMR (DMSO-D₆) δ: 8.18-8.16 (1H, m), 8.12 (1H, br s), 8.05 (1H, dd, J = 8.0, 1.5 Hz), 7.96-7.92 (2H, m), 7.69-7.66 (1H, m), 7.57-7.53 (1H, m), 7.47-7.42 (2H, m), 7.35 (1H, s). 30

¹H-NMR (DMSO-D₆) δ: 8.63-8.55 (1H, m), 8.15-8.11 (1H, m), 8.00 (1H, dd, J = 7.9, 1.6 Hz), 7.96-7.91 (2H, m), 7.69- 7.66 (1H, m), 7.57-7.52 (1H, m), 7.46-7.42 (1H, m), 7.36 (1H, s), 2.81 (3H, d, J = 4.6 Hz). 31

¹H-NMR (DMSO-D₆) δ: 7.94-7.91 (2H, m), 7.68-7.65 (1H, m), 7.63-7.62 (1H, m), 7.58-7.52 (2H, m), 7.46-7.41 (1H, m), 7.37 (1H, s), 3.00 (3H, br s), 2.96 (3H, br s). 32

¹H-NMR (DMSO-D₆) δ: 13.52 (1H, br s), 8.23 (1H, d, J = 7.5 Hz), 7.84-7.80 (2H, m), 7.71- 7.67 (1H, m), 7.54-7.42 (3H, m), 7.31 (1H, br s). 33

¹H-NMR (DMSO-D₆) δ: 8.11 (1H, br s), 7.94 (1H, d, J = 7.7 Hz), 7.72-7.64 (3H, m), 7.50- 7.38 (4H, m), 7.28 (1H, s). 34

¹H-NMR (DMSO-D₆) δ: 8.62-8.54 (1H, m), 7.77-7.74 (1H, m), 7.72-7.69 (1H, m), 7.68-7.64 (1H, m), 7.50-7.38 (4H, m), 7.29 (1H, s), 2.86 (3H, d, J = 4.4 Hz). 35

¹H-NMR (DMSO-D₆) δ: 7.71-7.66 (2H, m), 7.53-7.34 (5H, m), 7.33 (1H, br s), 3.14 (3H, s), 2.76 (3H, s).

TABLE 1-6 compound No. structural formula NMR 36

¹H-NMR (DMSO-D₆) δ: 8.73 (1H, d, J = 2.2 Hz), 8.11 (1H, d, J = 1.5 Hz), 7.93-7.89 (1H, m), 7.76-7.73 (1H, m), 7.67-7.56 (2H, m), 7.66 (1H, s). 37

¹H-NMR (DMSO-D₆) δ: 7.78-7.73 (2H, m), 7.60-7.57 (1H, m), 7.48-7.44 (1H, m), 7.32-7.28 (1H, m), 7.25 (1H, s), 7.17- 7.15 (1H, m), 7.07 (1H, dd, J = 8.3, 2.6 Hz), 3.83 (3H, s). 38

¹H-NMR (DMSO-D₆) δ: 9.82 (1H, s), 7.67 (1H, d, J = 7.4 Hz), 7.63 (1H, d, J = 8.3 Hz), 7.58-7.54 (1H, m), 7.45-7.40 (1H, m), 7.28-7.23 (1H, m), 7.15 (1H, s), 7.07-7.04 (1H, m), 6.87 (1H, dd, J = 8.1, 2.3 Hz). 39

¹H-NMR (DMSO-D₆) δ: 7.80 (1H, d, J = 7.4 Hz), 7.75 (1H, d, J = 7.7 Hz), 7.63-7.59 (1H, m), 7.50-7.46 (2H, m), 7.37-7.32 (2H, m), 7.19 (1H, s), 2.69 (2H, q, J = 7.6 Hz), 1.22 (3H, t, J = 7.5 Hz). 40

¹H-NMR (DMSO-D₆) δ: 8.41 (1H, d, J = 0.9 Hz), 8.05-7.99 (2H, m), 7.81-7.77 (1H, m), 7.70- 7.66 (1H, m), 7.57-7.53 (1H, m), 7.47-7.42 (1H, m), 7.44 (1H, s), 3.92 (3H, s). 41

¹H-NMR (DMSO-D₆) δ: 13.23 (1H, br s), 8.38 (1H, d, J = 0.9 Hz), 8.02-7.97 (2H, m), 7.78- 7.74 (1H, m), 7.69-7.65 (1H, m), 7.57-7.52 (1H, m), 7.46- 7.41 (1H, m), 7.41 (1H, s). 42

¹H-NMR (DMSO-D₆) δ: 8.32 (1H, d, J = 1.1 Hz), 8.08 (1H, br s), 7.90-7.86 (2H, m), 7.71- 7.65 (2H, m), 7.57-7.53 (1H, m), 7.51 (1H, br s), 7.45-7.41 (1H, m), 7.35 (1H, s).

TABLE 1-7 compound No. structural formula NMR 43

¹H-NMR (DMSO-D₆) δ: 8.59-8.53 (1H, m), 8.26 (1H, d, J = 1.1 Hz), 7.89 (1H, d, J = 7.5 Hz) 7.82 (1H, dd, J = 7.9, 1.5 Hz), 7.72-7.69 (1H, m), 7.68- 7.65 (1H, m), 7.58-7.53 (1H, m), 7.45-7.40 (1H, m), 7.35 (1H, s), 2.83 (3H, d, J = 4.6 Hz). 44

¹H-NMR (DMSO-D₆) δ: 7.96-7.91 (2H, m), 7.69-7.64 (2H, m), 7.55-7.50 (1H, m), 7.44-7.37 (2H, m), 7.33 (1H, s), 3.03 (3H, br s), 2.94 (3H, br s). 45

¹H-NMR (DMSO-D₆) δ: 8.07-8.04 (1H, m), 7.98-7.94 (2H, m), 7.76-7.71 (1H, m), 7.62-7.57 (1H, m), 7.52-7.47 (1H, m), 7.41 (1H, s), 3.89 (3H, s), 2.71 (3H, s). 46

¹H-NMR (DMSO-D₆) δ: 7.93 (1H, d, J = 7.5 Hz), 7.64-7.60 (1H, m), 7.50-7.45 (1H, m), 7.40- 7.32 (2H, m), 7.27-7.23 (1H, m), 7.20 (1H, s), 7.17 (1H, d, J = 8.4 Hz), 3.98 (3H, s). 47

¹H-NMR (DMSO-D₆) δ: 7.87 (1H, d, J = 7.5 Hz), 7.63-7.59 (1H, m), 7.54-7.47 (2H, m), 7.46 (1H, d, J = 2.4 Hz), 7.40-7.35 (1H, m), 7.10 (1H, s), 6.92 (1H, dd, J = 8.4, 2.4 Hz), 3.85 (3H, s). 48

¹H-NMR (CDCl₃) δ: 8.29 (1H, d, J = 7.9 Hz), 7.91-7.84 (2H, m), 7.75-7.70 (1H, m), 7.50- 7.45 (1H, m), 7.42-7.38 (2H, m), 4.48 (2H, q, J = 7.1 Hz), 2.72 (1H, s), 1.45 (3H, t, J = 7.2 Hz). 49

¹H-NMR (DMSO-D₆) δ: 8.23-8.19 (1H, m), 7.98 (2H, d, J = 7.9 Hz), 7.79-7.75 (1H, m), 7.71- 7.66 (1H, m), 7.63-7.54 (2H, m), 7.55 (1H, s).

TABLE 1-8 compound No. structural formula NMR 50

¹H-NMR (CDCl₃) δ: 8.54 (1H, d, J = 1.5 Hz), 8.45 (1H, br s), 8.37-8.33 (1H, m), 7.79-7.74 (1H, m), 7.54-7.44 (2H, m), 4.03 (3H, s), 3.96 (3H, s), 3.03 (0H, s). 51

¹H-NMR (CDCl₃) δ: 7.76-7.72 (1H, m), 7.68-7.65 (1H, m), 7.64-7.61 (1H, m), 7.59 (1H, d, J = 7.7 Hz), 7.52-7.47 (1H, m), 7.42-7.34 (2H, m), 3.97 (1H, br s), 3.53 (1H, br s), 3.26 (1H, br s), 3.03-2.91 (3H, m), 1.26-1.10 (3H, m). 52

¹H-NMR (CDCl₃) δ: 7.75-7.72 (1H, m), 7.68-7.65 (1H, m), 7.63-7.61 (1H, m), 7.60 (1H, d, J = 7.7 Hz), 7.52-7.47 (1H, m), 7.42-7.36 (2H, m), 3.87 (1H, s), 3.75-3.22 (4H, m), 1.73-1.43 (6H, m). 53

¹H-NMR (CDCl₃) δ: 7.77-7.72 (2H, m), 7.69-7.65 (1H, m), 7.60-7.57 (1H, m), 7.52-7.47 (2H, m), 7.43-7.38 (1H, m), 4.36 (1H, br s), 3.62-3.35 (4H, m), 1.98-1.80 (4H, m). 54

¹H-NMR (CDCl₃) δ: 7.76-7-72 (1H, m), 7.68-7.65 (1H, m), 7.63-7.57 (2H, m), 7.52-7.47 (1H, m), 7.42-7.37 (1H, m), 7.36-7.32 (1H, m), 3.93 (1H, br s), 3.50 (2H, br s), 3.25 (2H, br s), 1.22 (3H, br s), 1.12 (3H, br 3). 55

¹H-NMR (DMSO-D₆) δ: 7.84 (1H, d, J = 8.1 Hz), 7.81 (1H, d, J = 7.4 Hz), 7.65-7.61 (1H, m), 7.53-7.48 (1H, m), 7.46-7.43 (1H, m), 7.39-7.34 (1H, m), 7.31-7.27 (1H, m). 56

¹H-NMR (CDCl₃) δ: 7.67-7.64 (1H, m), 7.61-7.58 (1H, m), 7.53-7.42 (4H, m), 7.37-7.33 (1H, m), 7.25-7.20 (2H, m), 7.17-7.12 (1H, m), 7.07-7.02 (2H, m), 3.50 (3H, s), 2.84 (1H, br s).

TABLE 1-9 compound No. structural formula NMR 57

¹H-NMR (CDCl₃) δ: 7.76-7.72 (1H, m), 7.69-7.66 (1H, m), 7.65-7.60 (2H, m), 7.53-7.48 (1H, m), 7.43-7.37 (2H, m), 4.33-3.47 (1H, m), 3.13-2.80 (3H, m), 2.33-1.93 (4H, m), 1.79-1.37 (2H, m). 58

¹H-NMR (CDCl₃) δ: 7.83-7.80 (1H, m), 7.78-7.73 (1H, m), 7.71-7.67 (2H, m), 7.66-7.62 (1H, m), 7.52-7.47 (1H, m), 7.43-7.39 (1H, m), 4.39-3.99 (5H, m), 2.37-2.26 (2H, m). 59

¹H-NMR (DMSO-D₆) δ: 8.07 (1H, d, J = 7.7 Hz), 7.87-7.84 (1H, m), 7.83 (1H, dd, J = 7.8, 1.0 Hz), 7.72-7.68 (1H, m), 7.54- 7.44 (3H, m), 7.36 (1H, s), 4.36 (2H, t, J = 6.6 Hz), 1.83-1.73 (2H, m), 0.99 (3H, t, J = 7.4 Hz). 60

¹H-NMR (DMSO-D₆) δ: 8.09 (1H, d, J = 7.4 Hz), 7.86-7.83 (1H, m), 7.79 (1H, dd, J = 7.9, 1.2 Hz), 7.71-7.68 (1H, m), 7.55- 7.44 (3H, m), 7.35 (1H, s), 5.33-5.23 (1H, m), 1.40 (3H, d, J = 3.7 Hz), 1.38 (3H, d, J = 3.7 Hz). 61

¹H-NMR (DMSO-D₆) δ: 8.36 (1H, d, J = 7.4 Hz), 8.14-8.13 (1H, m), 8.09 (1H, d, J = 1.4 Hz), 7.79-7.76 (1H, m), 7.68-7.64 (1H, m), 7.66 (1H, s), 7.61- 7.57 (1H, m), 3.92 (3H, s). 62

¹H-NMR (DMSO-D₆) δ: 9.81 (1H, s), 7.74 (1H, d, J = 7.5 Hz), 7.61-7.57 (1H, m), 7.49-7.44 (1H, m), 7.43-7.39 (1H, m), 7.38-7.33 (1H, m), 7.18 (1H, d, J = 2.2 Hz), 6.99 (1H, s), 6.75 (1H, dd, J = 8.3, 2.3 Hz). 63

¹H-NMR (DMSO-D₆) δ: 10.27 (1H, s), 7.94 (1H, d, J = 7.4 Hz), 7.61-7.57 (1H, m), 7.48-7.43 (1H, m), 7.33-7.28 (1H, m), 7.21-7.17 (1H, m), 7.12-7.08 (2H, m), 6.94 (1H, dd, J = 8.1, 0.9 Hz).

TABLE 1-10 compound No. structural formula NMR 64

¹H-NMR (DMSO-D₆) δ: 8.00-7.97 (1H, m), 7.92-7-89 (2H, m), 7.78-7.75 (1H, m), 7.66-7.60 (2H, m), 7.56-7.52 (1H, m), 7.48 (1H, s). 65

¹H-NMR (DMSO-D₆) δ: 7.74-7.65 (2H, m), 7.53-7.39 (5H, m), 7.35 (1H, s), 3.42 (3H, br s), 3.36 (3H, br s). 66

¹H-NMR (DMSO-D₆) δ: 7.96 (1H, d, J = 7.5 Hz), 7.64-7.60 (1H, m), 7.51-7.46 (1H, m), 7.37- 7.32 (2H, m), 7.25-7.22 (1H, m), 7.18 (1H, s), 7.14 (1H, d, J = 8.2 Hz), 4.23 (2H, q, J = 7.0 Hz), 1.48 (3H, t, J = 6.9 Hz). 67

¹H-NMR (DMSO-D₆) δ: 7.85 (1H, d, J = 7.5 Hz), 7.62-7.59 (1H, m), 7.53-7.47 (2H, m), 7.45 (1H, d, J = 2.4 Hz), 7.39-7.35 (1H, m), 7.08 (1H, s), 6.90 (1H, dd, J = 8.4, 2.4 Hz), 4.13 (2H, q, J = 6.9 Hz), 1.37 (3H, t, J = 6.9 Hz). 68

¹H-NMR (DMSO-D₆) δ: 7.89-7.79 (3H, m), 7.70-7.66 (1H, m), 7.54-7.40 (3H, m), 7.31 (1H, s), 2.71 (3H, s). 69

¹H-NMR (DMSO-D₆) δ: 7.82 (1H, d, J = 7.7 Hz), 7.79 (1H, d, J = 7.9 Hz), 7.65-7.61 (2H, m), 7.52-7.47 (1H, m), 7.45-7.41 (1H, m), 7.39-7.34 (1H, m), 7.21 (1H, s), 5.33 (1H, t, J = 5.7 Hz), 4.57 (2H, d, J = 5.6 Hz). 70

¹H-NMR (CDCl₃) δ: 7.70-7.66 (1H, m), 7.64-7.60 (1H, m), 7.56 (1H, d, J = 7.9 Hz), 7.52-7.50 (1H, m), 7.47-7.43 (1H, m), 7.34-7.27 (2H, m), 2.70 (1H, br s), 2.69-2.63 (2H, m), 1.74-1.64 (2H, m), 0.97 (3H, t, J = 7.3 Hz).

TABLE 1-11 compound No. structural formula NMR 71

¹H-NMR (CDCl₃) δ: 7.70-7.66 (1H, m), 7.64-7.61 (1H, m), 7.59-7.55 (2H, m), 7.48-7.43 (1H, m), 7.35-7.30 (2H, m), 3.05-2.93 (1H, m), 2.70 (1H, s), 1.31 (3H, d, J = 1.4 Hz), 1.29 (3H, d, J = 1.4 Hz). 72

¹H-NMR (DMSO-D₆) δ: 8.59-8.55 (1H, m), 8.26 (1H, d, J = 1.3 Hz), 7.90 (1H, d, J = 7.5 Hz), 7.83 (1H, dd, J = 7.9, 1.5 Hz), 7.72-7.65 (2H, m), 7.57- 7.53 (1H, m), 7.45-7.40 (1H, m), 7.35 (1H, s), 3.37-3.29 (2H, m), 1.16 (3H, t, J = 7.2 Hz). 73

¹H-NMR (DMSO-D₆) δ: 8.35-8.31 (1H, m), 8.27-8.25 (1H, m), 7.91 (1H, d, J = 7.5 Hz), 7.83 (1H, dd, J = 7.9, 1.5 Hz), 7.72-7.65 (2H, m), 7.57-7.53 (1H, m), 7.45-7.40 (1H, m), 7.35 (1H, s), 4.17-4.08 (1H, m), 1.21 (3H, s), 1.19 (3H, s). 74

¹H-NMR (DMSO-D₆) δ: 7.83 (1H, d, J = 7.7 Hz), 7.69-7.65 (1H, m), 7.58-7.50 (3H, m), 7.41- 7.35 (2H, m), 7.17 (1H, s), 5.43 (1H, t, J = 5.4 Hz), 4.91-4.81 (2H, m). 75

¹H-NMR (DMSO-D₆) δ: 7.86-7.81 (2H, m), 7.66-7.62 (1H, m), 7.61-7.58 (1H, m), 7.53-7.48 (1H, m), 7.46-7.43 (1H, m), 7.40-7.36 (1H, m), 7.24 (1H, s), 4.49 (2H, s), 3.34 (3H, s). 76

¹H-NMR (DMSO-D₆) δ: 8.18-8.15 (2H, m), 8.05-7.98 (2H, m), 7.72-7.68 (1H, m), 7.60-7.55 (1H, m), 7.51-7.46 (1H, m), 7.44 (1H, s), 2.64 (3H, s). 77

¹H-NMR (DMSO-D₆) δ: 7.92 (2H, d, J = 7.4 Hz), 7.73-7.61 (3H, m), 7.57-7.52 (1H, m), 7.46- 7.41 (1H, m), 7.39 (0.5H, s), 7.35 (0.5H, s), 4.23-3.94 (1H, m), 3.60-3.47 (1H, m), 3.38- 3.29 (1H, m), 2.14-2.03 (1H, m), 1.97-1.82 (1H, m), 1.78- 1.66 (1H, m), 1.62-1.50 (1H, m), 1.33-1.20 (2H, m), 0.95- 0.77 (1H, m).

TABLE 1-12 compound No. structural formula NMR 78

¹H-NMR (DMSO-D₆) δ: 8.13-8.11 (1H, m), 8.03-7.92 (3H, m), 7.69-7.66 (1H, m), 7.58-7.53 (1H, m), 7.48-7.43 (1H, m), 7.41 (1H, s), 4.48-4.42 (2H, m), 4.02-3.97 (2H, m). 79

¹H-MMR (DMSO-D₆) δ: 7.96-7.91 (2H, m), 7.87-7.85 (1H, m), 7.78-7.74 (1H, m), 7.69-7.65 (1H, m), 7.57-7.53 (1H, m), 7.47-7.43 (1H, m), 7.39 (1H, s), 5.76 (1H, d, J = 6.0 Hz), 4.56-4.43 (2H, m), 4.34-4.22 (1H, m), 4.13-4.00 (1H, m), 3.89-3.71 (1H, m). 80

¹H-NMR (CDCl₃) δ: 7.64-7.60 (1H, m), 7.51-7.47 (2H, m), 7.42- 7.37 (1H, m), 7.23-7.18 (1H, m), 7.06-7.03 (1H, m), 6.76 (1H, dd, J = 8.5, 2.4 Hz), 3.03 (6H, s), 2.69 (1H, br s). 81

¹H-NMR (DMSO-D₆) δ: 7.80-7.76 (2H, m), 7.69-7.66 (1H, m), 7.64-7.61 (1H, m), 7.52-7.40 (3H, m), 7.32 (1H, s), 3.16- 2.97 (2H, m), 1.17 (3H, t, J = 7.2 Hz). 82

¹H-NMR (DMSO-D₆) δ: 7.75 (1H, d, J = 7.7 Hz), 7.69-7.65 (1H, m), 7.64-7.60 (1H, m), 7.56-7.48 (2H, m), 7.43-7.36 (2H, m), 7.22 (1H, s), 4.79 (1H, d, J = 12.3 Hz), 4.74 (1H, d, J = 12.3 Hz), 3.40 (3H, s). 83

¹H-NMR (DMSO-D₆) δ: 7.83-7.78 (2H, m), 7.72-7.66 (2H, m), 7.55-7.51 (1H, m), 7.49-7.40 (2H, m), 7.33 (1H, s), 2.62- 2.55 (1H, m), 1.26-1.14 (4H, m). 84

¹H-NMR (DMSO-D₆) δ: 7.96-7.92 (1H, m), 7.65-7.62 (1H, m), 7.54-7.49 (1H, m), 7.38-7.30 (3H, m), 7.23 (1H, dd, J = 7.1, 2.0 Hz), 7.13 (1H, s), 2.76 (6H, s).

TABLE 1-13 compound No. structural formula NMR 85

¹H-NMR (DMSO-D₆) δ: 7.96 (1H, d, J = 7.7 Hz), 7.63-7.61 (1H, m), 7.49-7.44 (1H, m), 7.33-7.24 (2H, m), 7.05-7.00 (1H, m), 6.82 (2H, br s), 6.67 (2H, s), 2.88 (3H, s). 86

¹H-NMR (DMSO-D₆) δ: 7.96-7.92 (2H, m), 7.90-7.87 (1H, m), 7.80- 7.76 (1H, m), 7.70-7.66 (1H, m), 7.58-7.53 (1H, m), 7.48-7.43 (1H, m), 7.40 (1H, br s), 4.55-4.40 (1H, m), 4.32-4.23 (2H, m), 4.22- 4.11 (1H, m), 3.97-3.78 (1H, m), 3.24 (3H, s). 87

¹H-NMR (DMSO-D₆) δ: 7.94 (2H, d, J = 7.9 Hz), 7.88-7.86 (1H, m), 7.80-7.76 (1H, m), 7.69-7.65 (1H, m), 7.57-7.53 (1H, m), 7.47-7.42 (1H, m), 7.40 (1H, s), 4.83 (1H, t, J = 5.3 Hz), 4.40-4.31 (1H, m), 4.10-4.03 (2H, m), 3.84-3.78 (1H, m), 3.56 (2H, t, J = 5.7 Hz), 2.80-2.69 (1H, m). 88

¹H-NMR (DMSO-D₆) δ: 8.14-8.11 (1H, m), 8.01-7.96 (1H, m), 7.92- 7.86 (2H, m), 7.69-7.63 (1H, m), 7.57-7.50 (1H, m), 7.45-7.39 (1H, m), 7.32 (1H, s), 4.41-4.33 (1H, m), 3.95-3.85 (1H, m), 3.65-3.54 (1H, m), 3.19-3.07 (1H, m), 2.11- 1.94 (1H, m), 0.95 (3H, d, J = 6.4 Hz). 89

¹H-NMR (CDCl₃) δ: 7.67-7.63 (1H, m), 7.57-7.53 (2H, m), 7.45- 7.41 (1H, m), 7.30-7.23 (2H, m), 6.98 (1H, dd, J = 8.3, 2.3 Hz), 4.10 (2H, q, J = 7.0 Hz), 2.67 (1H, s), 1.44 (3H, t, J = 6.9 Hz). 90

¹H-NMR (DMSO-D₆) δ: 7.95-7.91 (2H, m), 7.87-7.71 (2H, m), 7.69- 7.65 (1H, m), 7.57-7.52 (1H, m), 7.47-7.42 (1H, m), 7.40 (0.5H, s), 7.36 (0.5H, s), 4.84-3.87 (3H, m), 2.46-2.31 (1H, m), 1.94-1.74 (1H, m), 1.55-1.35 (2H, m), 1.21-1.00 (1H, m). 91

¹H-NMR (DMSO-D₆) δ: 7.93- 7.88 (1H, m), 7.74-7.68 (2H, m), 7.60-7.54 (2H, m), 7.48-7.43 (1H, m), 7.32 (1H, s), 4.39-4.29 (2H, m), 4.12-4.02 (2H, m), 2.68 (3H, s), 2.34-2.23 (2H, m).

TABLE 1-14 compound No. structural formula NMR 92

¹H-NMR (DMSO-D₆) δ: 8.64 (1H, s), 7.79 (1H, d, J = 7.3 Hz), 7.72-7.68 (1H, m), 7.59-7.56 (2H, m), 7.53-7.49 (1H, m), 7.44-7.40 (2H, m), 7.35 (1H, s), 7.11-7.06 (1H, m). 93

¹H-NMR (DMSO-D₆) δ: 7.80- 7.76 (1H, m), 7.75-7.11 (1H, m), 7.69-7.66 (1H, m), 7.52-7.39 (4H, m), 7.32 (1H, s), 3.50-3.42 (1H, m), 1.18 (3H, d, J = 7.0 Hz), 1.13 (3H, d, J = 7.0 Hz). 94

¹H-NMR (DMSO-D₆) δ: 8.32 (1H, d, J = 7.7 Hz), 7.83-7.81 (1H, m), 7.78-7.73 (2H, m), 7.65-7.61 (1H, m), 7.58-7.52 (1H, m), 7.57 (1H, s), 4.39-4.33 (2H, m), 4.11-4.04 (2H, m), 2.34-2.24 (2H, m). 95

¹H-NMR (DMSO-D₆) δ: 7.73- 7.66 (2H, m), 7.59-7.54 (1H, m), 7.46-7.41 (1H, m), 7.29-7.23 (1H, m), 7.17 (1H, br s), 6.99 (1H, br s), 4.64 (2H, br s), 2.81 (3H, br s). 96

¹H-NMR (CDCl₃) δ: 7.74-7.65 (3H, m), 7.54-7.48 (2H, m), 7.43-7.37 (1H, m), 7.32-7.27 (1H, m), 3.29 (3H, br s), 3.10 (1H, br s), 1.91 (3H, br s). 97

¹H-NMR (DMSO-D₆) δ: 7.96 (1H, d, J = 7.9 Hz), 7.91 (1H, d, J = 7.4 Hz), 7.89-7.87 (1H, m), 7.83 (1H, dd, J = 7.9, 1.6 Hz), 7.73-7.69 (2H, m), 7.68- 7.64 (1H, m), 7.56-7.49 (3H, m), 7.44-7.38 (2H, m), 7.35 (1H, s). 98

¹H-NMR (DMSO-D₆) δ: 8.06 (1H, d, J = 7.9 Hz), 8.02-7.99 (2H, m), 7.92 (1H, dd, J = 7.9, 1.6 Hz), 7.79-7.75 (2H, m), 7.74-7.69 (2H, m), 7.63-7.57 (3H, m), 7.52-7.47 (2H, m).

TABLE 1-15 compound No. structural formula NMR 99

¹H-NMR (DMSO-D₆) δ: 8.18- 8.16 (1H, m), 8.09-8.00 (4H, m), 7.79-7.77 (1H, m), 7.73-7.70 (1H, m), 7.62-7.57 (1H, m), 7.52-7.47 (2H, m), 7.36-7.33 (1H, m). 100

¹H-NMR (DMSO-D₆) δ: 10.09 (1H, s), 8.10-8.08 (1H, m), 7.71 (1H, d, J = 7.4 Hz), 7.64-7.61 (1H, m), 7.57-7.47 (3H, m), 7.41-7.36 (1H, m), 7.14 (1H, s), 2.37 (2H, q, J = 7.6 Hz), 1.11 (3H, t, J = 7.5 Hz). 101

¹H-NMR (DMSO-D₆) δ: 10.05 (1H, s), 8.12 (1H, d, J = 1.6 Hz), 7.72 (1H, d, J = 7.7 Hz), 7.63 (1H, d, J = 7.4 Hz), 7.57-7.48 (3H, m), 7.41-7.37 (1H, m), 7.15 (1H, s), 2.69-2.58 (1H, m), 1.13 (6H, d, J = 6.7 Hz). 102

¹H-NMR (CDCl₃) δ: 8.61 (1H, d, J = 2.3 Hz), 8.44-8.42 (1H, m), 7.89-7.85 (2H, m), 7.77 (1H, d, J = 13.9 Hz), 7.72 (1H, d, J = 7.9 Hz), 7.69 (1H, d, J = 7.7 Hz), 7.60-7.57 (1H, m), 7.53-7.49 (1H, m), 7.43- 7.38 (1H, m), 7.33 (1H, dd, J = 8.0, 4.8 Hz), 4.49 (1H, br s). 103

¹H-NMR (CDCl₃) δ: 8.58-8.55 (2H, m), 7.87-7.85 (1H, m), 7.78-7.69 (4H, m), 7.54-7.47 (3H, m), 7.43-7.38 (1H, m), 4.19 (1H, br s). 104

¹H-NMR (DMSO-D₆) δ: 7.96- 7.90 (2H, m), 7.87 (1H, s), 7.79- 7.74 (1H, m), 7.69-7.64 (1H, m), 7.57-7.52 (1H, m), 7.47- 7.41 (1H, m), 7.38 (1H, s), 4.52-4.43 (1H, m), 4.37-4.23 (2H, m), 4.21-4.11 (1H, m), 3.89-3.82 (1H, m), 3.42 (2H, q, J = 6.9 Hz), 1.13 (3H, t, J = 7.0 Hz). 105

¹H-NMR (DMSO-D₆) δ: 7.97- 7.91 (2H, m), 7.88 (1H, s), 7.80-7.76 (1H, m), 7.69-7.65 (1H, m), 7.58-7.53 (1H, m), 7.47-7.42 (1H, m), 7.39 (1H, br s), 4.54-4.43 (1H, m), 4.37- 4.24 (2H, m), 4.22-4.12 (1H, m), 3.90-3.83 (1H, m), 3.36- 3.27 (2H, m), 1.58-1.48 (2H, m), 0.88 (3H, t, J = 7.4 Hz).

TABLE 1-16 compound No. structural formula NMR 106

¹H-NMR (DMSO-D₆) δ: 7.97- 7.91 (2H, m), 7.90-7.86 (1H, m), 7.80-7.76 (1H, m), 7.69-7.65 (1H, m), 7.58-7.52 (1H, m), 7.48- 7.42 (1H, m), 7.39 (1H, br s), 4.53-4.42 (1H, m), 4.41-4.34 (1H, m), 4.32-4.24 (1H, m), 4.21-4.12 (1H, m), 3.92-3.82 (1H, m), 3.55- 3.49 (2H, m), 3.48-3.43 (2H, m), 3.25 (3H, s). 107

¹H-NMR (DMSO-D₆) δ: 12.73 (1H, br s), 7.97-7.92 (2H, m), 7.89-7.86 (1H, m), 7.80-7.75 (1H, m), 7.69-7.65 (1H, m), 7.58-7.53 (1H, m), 7.48-7.42 (1H, m), 7.40 (1H, br s), 4.53- 4.42 (2H, m), 4.33-4.19 (2H, m), 4.07 (2H, s), 3.98-3.90 (1H, m). 108

¹H-NMR (DMSO-D₆) δ: 7.96- 7.92 (2H, m), 7.89-7.86 (1H, m), 7.79-7.76 (1H, m), 7.70-7.65 (1H, m), 7.58-7.53 (1H, m), 7.48-7.43 (1H, m), 7.40 (1H, s), 4.67 (1H, t, J = 5.3 Hz), 4.54-4.45 (1H, m), 4.41-4.35 (1H, m), 4.32-4.24 (1H, m), 4.21-4.13 (1H, m), 3.94-3.84 (1H, m), 3.53-3.48 (2H, m), 3.45-3.40 (2H, m). 109

¹H-NMR (DMSO-D₆) δ: 8.21- 8.17 (2H, m), 8.02 (1H, d, J = 8.3 Hz), 8.00-7.97 (1H, m), 7.71-7.68 (1H, m), 7.60-7.55 (1H, m), 7.51-7.46 (1H, m), 7.43 (1H, s), 3.92-3.83 (1H, m), 1.99-1.88 (2H, m), 1.84-1.70 (2H, m), 1.66-1.61 (4H, m). 110

¹H-NMR (DMSO-D₆) δ: 7.73 (2H, d, J = 8.1 Hz), 7.60-7.56 (1H, m), 7.47-7.43 (1H, m), 7.31-7.27 (1H, m), 7.21 (1H, s), 7.14-7.11 (1H, m), 7.04 (1H, dd, J = 8.3, 2.3 Hz), 4.71-4.61 (1H, m), 1.31 (3H, d, J = 4.6 Hz), 1.29 (3H, d, J = 4.4 Hz). 111

¹H-NMR (DMSO-D₆) δ: 8.20 (1H, d, J = 7.9 Hz), 7.81-7.78 (1H, m), 7.74-7.71 (1H, m), 7.70-7.66 (1H, m), 7.52-7.41 (3H, m), 7.32 (1H, s), 4.55- 4.49 (2H, m), 4.16-4.10 (2H, m). 112

¹H-NMR (CDCl₃) δ: 8.54-8.52 (1H, m), 8.18-8.16 (1H, m), 8.04 (1H, dd, J = 7.9, 1.8 Hz), 7.77-7.64 (4H, m), 7.61- 7.58 (1H, m), 7.47-7.43 (1H, m), 7.39-7.35 (1H, m), 7.17- 7.13 (1H, m), 4.05 (1H, br s).

TABLE 1-17 compound No. structural formula NMR 113

¹H-NMR (DMSO-D₆) δ: 8.45 (1H, d, J = 7.7 Hz), 7.76-7.67 (3H, m), 7.63-7.58 (1H, m), 7.53-7.48 (1H, m), 7.40 (1H, br s), 7.37-7.33 (1H, m). 114

¹H-NMR (DMSO-D₆) δ: 8.50- 8.47 (1H, m), 7.91 (1H, d, J = 1.3 Hz), 7.87-7.84 (1H, m), 7.76-7.73 (1H, m), 7.67-7.62 (1H, m), 7.58-7.53 (1H, m), 7.55 (1H, s), 4.41-4.30 (2H, m), 4.14-4.02 (2H, m), 2.34- 2.23 (2H, m). 115

¹H-NMR (CDCl₃) δ: 7.78-7.64 (3H, m), 7.61-7.57 (2H, m), 7.51-7.46 (1H, m), 7.44-7.38 (1H, m), 5.34 (0.5H, br s), 5.16 (0.5H, br s), 4.48-3.93 (7H, m), 3.76 (3H, s). 116

¹H-NMR (DMSO-D₆) δ: 7.94 (2H, d, J = 7.7 Hz), 7.88-7.87 (1H, m), 7.79-7.76 (1H, m), 7.69-7.65 (1H, m), 7.58-7.53 (1H, m), 7.47-7.43 (1H, m), 7.40 (1H, s), 7.36 (1H, br s), 7.27 (1H, br s), 4.55-4.45 (1H, m), 4.45-4.39 (1H, m), 4.31- 4.21 (2H, m), 4.01-3.92 (1H, m), 3.83 (2H, s). 117

¹H-NMR (DMSO-D₆) δ: 7.96- 7.93 (2H, m), 7.89-7.87 (1H, m), 7.84 (1H, br s), 7.80-7.76 (1H, m), 7.69-7.66 (1H, m), 7.58- 7.53 (1H, m), 7.48-7.43 (1H, m), 7.40 (1H, br s), 4.58-4.46 (1H, m), 4.45-4.38 (1H, m), 4.34-4.17 (2H, m), 4.01-3.91 (1H, m), 3.87 (2H, s), 2.62 (3H, d, J = 4.6 Hz). 118

¹H-NMR (DMSO-D₆) δ: 7.96- 7.92 (2H, m), 7.88-7.87 (1H, m), 7.79-7.76 (1H, m), 7.69-7.66 (1H, m), 7.58-7.53 (1H, m), 7.47-7.43 (1H, m), 7.40 (1H, br s), 4.54-4.39 (2H, m), 4.32-4.17 (2H, m), 4.20 (2H, s), 3.99-3.87 (1H, m), 2.89 (3H, s), 2.81 (3H, s). 119

¹H-NMR (DMSO-D₆) δ: 8.15- 8.11 (1H, m), 8.08-8.05 (1H, m), 8.03-7.96 (2H, m), 7.72-7.68 (1H, m), 7.60-7.55 (1H, m), 7.51-7.46 (1H, m), 7.44 (1H, s), 4.23-4.14 (1H, m), 2.33- 2.23 (4H, m), 2.13-2.00 (1H, m), 1.87-1.75 (1H, m).

TABLE 1-18 compound No. structural formula NMR 120

¹H-NMR (CDCl₃) δ: 7.83-7.63 (5H, m), 7.53-7.48 (1H, m), 7.44-7.39 (1H, m), 4.58-4.06 (5H, m), 3.82-3.72 (3H, m), 3.52-3.40 (1H, m). 121

¹H-NMR (DMSO-D₆) δ: 7.94 (2H, d, J = 7.7 Hz), 7.88-7.86 (1H, m), 7.80-7.76 (1H, m), 7.69-7.66 (1H, m), 7.58-7.53 (1H, m), 7.48-7.43 (1H, m), 7.41 (1H, br s), 4.58-3.99 (4H, m), 3.55-3.43 (1H, m). 122

¹H-NMR (DMSO-D₆) δ: 8.03 (1H, d, J = 1.5 Hz), 7.98 (1H, br s), 7.86-7.83 (1H, m), 7.73- 7.68 (1H, m), 7.53-7.46 (3H, m), 4.43-4.34 (2H, m), 4.13- 4.06 (2H, m), 2.75 (3H, s), 2.34-2.26 (2H, m). 123

¹H-NMR (DMSO-D₆) δ: 7.94 (2H, d, J = 7.9 Hz), 7.89-7.86 (1H, m), 7.80-7.75 (1H, m), 7.69-7.66 (1H, m), 7.58-7.53 (1H, m), 7.52 (1H, s), 7.48- 7.43 (1H, m), 7.42-7.40 (1H, m), 7.09 (1H, br s), 4.48- 4.40 (1H, m), 4.37-4.30 (1H, m), 4.22-4.14 (1H, m), 4.08- 4.00 (1H, m), 3.42-3.35 (1H, m). 124

¹H-NMR (DMSO-D₆) δ: 8.02- 7.97 (1H, m), 7.94 (2H, d, J = 7.7 Hz), 7.88-7.86 (1H, m), 7.80-7.75 (1H, m), 7.69-7.65 (1H, m), 7.58-7.53 (1H, m), 7.47-7.43 (1H, m), 7.42-7.39 (1H, m), 4.49-4.40 (1H, m), 4.37-4.29 (1H, m), 4.22-4.14 (1H, m), 4.08-4.01 (1H, m), 3.41-3.34 (1H, m), 2.62 (3H, d, J = 4.6 Hz). 125

¹H-NMR (CDCl₃) δ: 7.89 (0.5H, br s), 7.81 (0.5H, br s), 7.78-7.63 (4H, m), 7.51-7.46 (1H, m), 7.43-7.37 (1H, m), 4.71-4.62 (1H, m), 4.49 (0.5H, br s), 4.38-3.98 (3.5H, m), 3.63-3.48 (1H, m), 2.97 (3H, s), 2.92-2.85 (3H, m). 126

¹H-NMR (CDCl₃) δ: 7.72 (1H, d, J = 7.4 Hz), 7.68 (1H, d, J = 7.7 Hz), 7.54-7.36 (6H, m), 7.32 (1H, dd, J = 7.7, 0.7 Hz), 7.29-7.24 (1H, m), 7.17-7.12 (1H, m), 6.82 (1H, d, J = 7.9 Hz), 2.04 (1H, br s).

TABLE 1-19 compound No. structural formula NMR 127

¹H-NMR (DMSO-D₆) δ: 7.96- 7.91 (2H, m), 7.68-7.63 (2H, m), 7.59-7.52 (2H, m), 7.46-7.41 (1H, m), 7.39 (1H, br s), 3.82-3.35 (8H, m). 128

¹H-NMR (DMSO-D₆) δ: 7.73 (2H, d, J = 8.1 Hz), 7.60-7.57 (1H, m), 7.48-7.43 (1H, m), 7.32-7.27 (1H, m), 7.22 (1H, s), 7.08-7.05 (1H, m), 6.96 (1H, dd, J = 8.3, 2.3 Hz), 4.79-4.71 (1H, m), 2.48-2.41 (2H, m), 2.13-2.01 (2H, m), 1.85-1.75 (1H, m), 1.74-1.64 (1H, m). 129

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, d, J = 7.9 Hz), 7.94-7.90 (2H, m), 7.87 (1H, dd, J = 8.0, 1.7 Hz), 7.69-7.65 (1H, m), 7.59-7.51 (4H, m), 7.44- 7.40 (1H, m), 7.36 (1H, s), 7.28-7.21 (1H, m). 130

¹H-NMR (DMSO-D₆) δ: 9.46 (1H, br s), 7.76-7.72 (1H, m), 7.67-7.63 (1H, m), 7.54-7.48 (2H, m), 7.41-7.35 (3H, m), 7.26 (1H, s), 3.32 (1.5H, s), 3.29 (1.5H, s). 131

¹H-NMR (DMSO-D₆) δ: 8.39 (1H, d, J = 0.9 Hz), 8.10-8.07 (1H, m), 7.88 (1H, dd, J = 7.8, 1.2 Hz), 7.86-7.82 (1H, m), 7.73-7.69 (1H, m), 7.59- 7.54 (2H, m), 7.49-7.42 (2H, m), 7.36 (1H, s). 132

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, d, J = 7.9 Hz), 7.94-7.86 (3H, m), 7.78-7.76 (1H, m), 7.71-7.65 (2H, m), 7.57-7.52 (2H, m), 7.49-7.46 (1H, m), 7.44-7.40 (1H, m), 7.36 (1H, s). 133

¹H-NMR (CDCl₃) δ: 7.92-7.58 (5H, m), 7.52-7.47 (1H, m), 7.43-7.38 (1H, m), 5.81 (0.5H, br s), 5.54 (0.5H, br s), 4.22-4.09 (1H, m), 4.06- 3.93 (2H, m), 3.82-3.77 (0.5H, m), 3.68-3.62 (0.5H, m), 3.05-2.89 (1H, m), 2.05 (3H, s), 1.97 (3H, s).

TABLE 1-20 compound No. structural formula NMR 134

¹H-NMR (CDCl₃) δ: 8.79-8.75 (1H, m), 7.83-7.77 (1H, m), 7.73-7.66 (2H, m), 7.51-7.47 (1H, m), 7.41-7.37 (1H, m), 7.31-7.20 (3H, m), 7.14-7.07 (1H, m), 6.66 (1H, d, J = 7.9 Hz). 135 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.92- 7.89 (1H, m), 7.72-7.69 (2H, m), 7.59-7.54 (2H, m), 7.48-7.43 (1H, m), 7.31 (1H, s), 4.38- 4.29 (2H, m), 4.12-4.03 (2H, m), 2.68 (3H, s), 2.32-2.24 (2H, m). 136 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.92- 7.89 (1H, m), 7.73-7.68 (2H, m), 7.59-7.54 (2H, m), 7.48-7.43 (1H, m), 7.31 (1H, s), 4.39- 4.28 (2H, m), 4.11-4.02 (2H, m), 2.58 (3H, s), 2.32-2.23 (2H, m). 137

¹H-NMR (DMSO-D₆) δ: 7.96- 7.92 (1H, m), 7.92-7.85 (2H, m), 7.83-7.79 (1H, m), 7.69-7.64 (1H, m), 7.56-7.47 (3H, m), 7.43-7.37 (2H, m), 7.33 (1H, s), 7.24-7.20 (1H, m), 2.41 (3H, s). 138

¹H-NMR (CDCl₃) δ: 7.88-7.84 (1H, m), 7.73-7.68 (1H, m), 7.64-7.59 (1H, m), 7.44-7.38 (1H, m), 7.35-7.28 (2H, m), 7.22-7.19 (1H, m), 5.36-5.33 (1H, m), 5.09-5.07 (1H, m), 2.66 (1H, br s), 2.16 (3H, s). 139

¹H-NMR (DMSO-D₆) δ: 8.76 (2H, d, J = 5.5 Hz), 7.75 (1H, d, J = 7.5 Hz), 7.67 (1H, d, J = 7.5 Hz), 7.54-7.47 (3H, m), 7.37-7.32 (2H, m), 7.32 (1H, s), 7.28-7.23 (1H, m), 6.79 (1H, d, J = 7.7 Hz). 140

¹H-NMR (DMSO-D₆) δ: 9.52 (1H, s), 8.05-8.02 (1H, m), 7.94-7.90 (2H, m), 7.75-7.70 (1H, m), 7.64-7.59 (1H, m), 7.52-7.45 (2H, m), 7.44 (1H, s).

TABLE 1-21 compound No. structural formula NMR 141

¹H-NMR (DMSO-D₆) δ: 8.26- 8.23 (1H, m), 8.17 (1H, d, J = 1.4 Hz), 8.14-8.11 (1H, m), 7.82-7.78 (1H, m), 7.74-7.69 (2H, m), 7.65-7.61 (1H, m), 4.45-4.34 (2H, m), 4.14-4.05 (2H, m), 2.34-2.24 (2H, m). 142

¹H-NMR (DMSO-D₆) δ: 7.98- 7.94 (3H, m), 7.75-7.71 (1H, m), 7.65-7.60 (1H, m), 7.53-7.48 (2H, m), 7.46 (1H, s), 2.54 (3H, s). 143

¹H-NMR (CDCl₃) δ: 8.60-8.57 (1H, m), 8.21-8.18 (1H, m), 8.03-8.00 (1H, m), 7.81-7.77 (1H, m), 7.60-7.54 (2H, m), 7.51-7.47 (1H, m), 3.21 (3H, s), 2.96 (1H, br s). 144

¹H-NMR (CDCl₃) δ: 7.95-7.92 (1H, m), 7.74-7.70 (2H, m), 7.68-7.64 (2H, m), 7.51-7.47 (1H, m), 7.40-7.31 (3H, m), 7.11 (1H, dd, J = 5.1, 3.7 Hz), 2.79 (1H, br s). 145

¹H-NMR (CDCl₃) δ: 7.91-7.89 (1H, m), 7.70-7.66 (2H, m), 7.65-7.61 (2H, m), 7.52-7.49 (1H, m), 7.48-7.43 (1H, m), 7.43-7.38 (2H, m), 7.36-7.31 (1H, m), 2.91 (1H, br s). 146

¹H-NMR (DMSO-D₆) δ: 8.74 (1H, dd, J = 4.9, 1.5 Hz), 8.65 (1H, br s), 7.94-7.86 (1H, m), 7.74 (1H, d, J = 7.5 Hz), 7.67 (1H, d, J = 7.3 Hz), 7.60 (1H, dd, J = 7.9, 5.1 Hz), 7.52-7.48 (1H, m), 7.39- 7.32 (2H, m), 7.31 (1H, s), 7.26-7.22 (1H, m), 6.66 (1H, d, J = 7.7 Hz). 147

¹H-NMR (DMSO-D₆) δ: 8.13- 8.11 (1H, m), 7.84 (1H, d, J = 8.3 Hz), 7.82-7.79 (1H, m), 7.65 (1H, dd, J = 8.5, 2.0 Hz), 7.64-7.61 (1H, m), 7.51-7.47 (1H, m), 7.37-7.32 (1H, m), 7.27 (1H, s), 3.95-3.83 (2H, m), 2.56-2.51 (2H, m), 2.13- 2.05 (2H, m).

TABLE 1-22 compound No. structural formula NMR 148

¹H-NMR (CDCl₃) δ: 7.65-7.62 (1H, m), 7.53-7.50 (1H, m), 7.48 (1H, d, J = 8.4 Hz), 7.43-7.38 (1H, m), 7.26-7.20 (2H, m), 6.96 (1H, dd, J = 8.4, 2.4 Hz), 3.24-3.20 (4H, m), 2.78 (1H, br s), 1.76- 1.68 (4H, m), 1.63-1.57 (2H, m). 149

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, d, J = 7.9 Hz), 7.93-7.90 (1H, m), 7.80-7.78 (1H, m), 7.73-7.65 (2H, m), 7.62-7.52 (2H, m), 7.50-7.33 (5H, m). 150

¹H-NMR (CDCl₃) δ: 7.98-7.90 (2H, m), 7.70-7.65 (2H, m), 7.64-7.52 (3H, m), 7.84-7.40 (4H, m), 7.34 (1H, s). 151

¹H-NMR (CDCl₃) δ: 7.74-7.67 (4H, m), 7.52-7.43 (2H, m), 7.39-7.35 (1H, m), 7.32-7.27 (4H, m), 2.76 (1H, br s), 2.31 (3H, s). 152 (optically active form)

¹H-NMR (CDCl₃) δ: 7.82-7.76 (2H, m), 7.75-7.64 (1H, m), 7.53-7.48 (1H, m), 7.44-7.38 (2H, m), 4.48-3.99 (6H, m), 3.80-3.71 (2H, m), 3.53 (2H, br s), 2.66-2.50 (3H, m), 2.31 (0.5H, br s), 2.03 (0.5H, br s). 153 (optically active form)

¹H-NMR (CDCl₃) δ: 7.83-7.73 (3H, m), 7.53-7.38 (3H, m), 4.73-4.65 (1H, m), 4.43-4.32 (2H, m), 4.24-4.11 (1H, m), 3.93-3.86 (1H, m), 3.64-3.56 (1H, m), 2.98 (3H, s), 2.91 (3H, s), 2.64 (3H, s). 154

¹H-NMR (CDCl₃) δ: 8.31-8.30 (1H, m), 8.06-8.03 (1H, m), 7.96-7.94 (1H, m), 7.85-7.81 (1H, m), 7.75-7.69 (4H, m), 7.57-7.48 (2H, m), 7.41-7.36 (1H, m), 3.96 (3H, s), 2.94 (1H, br s).

TABLE 1-23 compound No. structural formula NMR 155

¹H-NMR (CDCl₃) δ: 8.40-8.38 (1H, m), 8.14-8.11 (1H, m), 7.98-7.95 (1H, m), 7.91-7.88 (1H, m), 7.77-7.69 (4H, m), 7.62-7.57 (1H, m), 7.54-7.49 (1H, m), 7.42-7.36 (1H, m), 2.04 (1H, br s). 156

¹H-NMR (DMSO-D₆) δ: 8.22- 8.20 (1H, m), 8.18 (1H, br s), 8.00-7.97 (2H, m), 7.94-7.85 (4H, m), 7.70-7.66 (1H, m), 7.61-7.52 (2H, m), 7.47 (1H, br s), 7.44-7.39 (1H, m), 7.38 (1H, s). 157

¹H-NMR (DMSO-D₆) δ: 8.65- 8.60 (1H, m), 8.17-8.14 (1H, m), 8.01-7.96 (2H, m), 7.94-7.84 (4H, m), 7.70-7.66 (1H, m), 7.61-7.57 (1H, m), 7.56-7.52 (1H, m), 7.44-7.40 (1H, m), 7.39 (1H, s), 2.83 (3H, d, J = 4.4 Hz). 158

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, d, J = 7.9 Hz), 7.93-7.90 (2H, m), 7.87 (1H, dd, J = 7.9, 1.9 Hz), 7.81-7.77 (1H, m), 7.71-7.69 (1H, m), 7.69- 7.65 (1H, m), 7.59-7.51 (2H, m), 7.44-7.39 (2H, m), 7.36 (1H, br s), 3.05-2.94 (6H, m). 159

¹H-NMR (DMSO-D₆) δ: 8.29 (1H, d, J = 7.7 Hz), 7.89 (2H, s), 7.78-7.72 (3H, m), 7.63-7.59 (1H, m), 7.55-7.42 (5H, m). 160

¹H-NMR (CDCl₃) δ: 7.63-7.59 (1H, m), 7.49-7.45 (2H, m), 7.40-7.36 (1H, m), 7.20-7.15 (1H, m), 6.89-6.87 (1H, m), 6.60 (1H, dd, J = 8.4, 2.2 Hz), 3.38-3.33 (4H, m), 2.67 (1H, s), 2.07-1.99 (4H, m). 161

¹H-NMR (DMSO-D₆) δ: 7.70- 7.66 (2H, m), 7.58-7.55 (1H, m), 7.45-7.40 (1H, m), 7.27-7.23 (1H, m), 7.19-7.18 (1H, m), 7.12 (1H, s), 7.06 (1H, dd, J = 8.4, 2.4 Hz), 3.78-3.74 (4H, m), 3.20-3.16 (4H, m).

TABLE 1-24 compound No. structural formula NMR 162

¹H-NMR (DMSO-D₆) δ: 7.69-7.63 (2H, m), 7.57-7.54 (1H, m), 7.44-7.40 (1H, m), 7.27-7.22 (1H, m), 7.19-7.16 (1H, m), 7.10 (1H, s), 7.05 (1H, dd, J = 8.5, 2.3 Hz), 3.23-3.18 (4H, m), 2.49-2.45 (4H, m), 2.23 (3H, s). 163

¹H-NMR (CDCl₃) δ: 7.67-7.63 (1H, m), 7.56-7.51 (2H, m), 7.45-7.40 (1H, m), 7.28-7.24 (2H, m), 6.97 (1H, dd, J = 8.3, 2.3 Hz), 3.62-3.57 (4H, m), 3.23-3.18 (4H, m), 2.77 (1H, br s), 1.49 (9H, s). 164

¹H-NMR (DMSO-D₆) δ: 9.11 (2H, br s), 7.72 (2H, d, J = 8.2 Hz), 7.60-7.56 (1H, m), 7.47-7.42 (1H, m), 7.30-7.26 (1H, m), 7.25-7.22 (1H, m), 7.11 (1H, dd, J = 8.5, 2.3 Hz), 4.96 (2H, br s), 3.46-3.41 (4H, m), 3.28-3.21 (4H, m). 165

¹H-NMR (DMSO-D₆) δ: 7.71-7.66 (2H, m), 7.58-7.54 (1H, m), 7.45-7.40 (1H, m), 7.28-7.23 (1H, m), 7.22-7.19 (1H, m), 7.15 (1H, s), 7.07 (1H, dd, J = 8.3, 2.1 Hz), 3.63-3.58 (4H, m), 3.30-3.11 (4H, m), 2.05 (3H, s). 166

¹H-NMR (DMSO-D₆) δ: 8.49 (1H, s), 7.69-7.65 (2H, m), 7.58-7.55 (1H, m), 7.46-7.41 (1H, m), 7.37-7.35 (1H, m), 7.31-7.23 (3H, m), 7.18-7.11 (4H, m), 6.91-6.87 (1H, m). 167

¹H-NMR (CDCl₃) δ: 7.86-7.32 (7H, m), 4.63-4.49 (1H, m), 3.76 (3H, s), 3.73-3.47 (2H, m), 2.38-2.16 (1H, m), 2.09-1.82 (3H, m). 168

¹H-NMR (DMSO-D₆) δ: 12.57 (1H, br s), 7.97-7.87 (2H, m), 7.77-7.73 (1H, m), 7.72-7.61 (2H, m), 7.58-7.50 (1H, m), 7.48-7.38 (2H, m), 4.47-4.37 (1H, m), 3.65-3.46 (2H, m), 2.35-2.22 (1H, m), 2.04-1.77 (3H, m).

TABLE 1-25 compound No. structural formula NMR 169

¹H-NMR (CDCl₃) δ: 7.69-7.66 (1H, m), 7.63-7.60 (1H, m), 7.57 (1H, d, J = 7.9 Hz), 7.55-7.54 (1H, m), 7.47-7.43 (1H, m), 7.34-7.29 (2H, m), 2.65 (1H, br s), 2.62-2.54 (1H, m), 1.95-1.83 (4H, m), 1.80-1.74 (1H, m), 1.49-1.38 (4H, m), 1.34-1.23 (1H, m). 170

¹H-NMR (DMSO-D₆) δ: 7.90-7.86 (2H, m), 7.75-7.74 (1H, m), 7.67-7.61 (2H, m), 7.54-7.50 (1H, m), 7.42-7.33 (3H, m), 7.28 (1H, br s), 7.15 (1H, d, J = 8.1 Hz), 7.09-7.05 (1H, m), 3.80 (3H, s). 171

¹H-NMR (CDCl₃) δ: 7.88-7.87 (1H, m), 7.74-7.64 (4H, m), 7.63-7.57 (2H, m), 7.52-7.48 (1H, m), 7.40-7.36 (1H, m), 7.19-7.13 (2H, m), 2.75 (1H, br s). 172

¹H-NMR (CDCl₃) δ: 7.89-7.87 (1H, m), 7.73-7.64 (4H, m), 7.60-7.56 (2H, m), 7.51-7.46 (1H, m), 7.38-7.33 (1H, m), 7.02-6.98 (2H, m), 3.87 (3H, s), 2.75 (1H, br s). 173

¹H-NMR (CDCl₃) δ: 7.88 (1H, d, J = 7.7 Hz), 7.73-7.67 (3H, m), 7.65-7.63 (1H, m), 7.58-7.53 (1H, m), 7.52-7.35 (5H, m), 4.15-4.05 (2H, m), 2.92 (1H, s), 1.04-0.99 (3H, m). 174

¹H-NMR (DMSO-D₆) δ: 8.22 (1H, br s), 7.97 (1H, d, J = 7.7 Hz), 7.90 (1H, br s), 7.80 (1H, br s), 7.71-7.67 (2H, m), 7.54-7.49 (1H, m), 7.48-7.43 (1H, m), 7.45 (1H, s), 4.40-4.32 (2H, m), 4.13-4.04 (2H, m), 2.34-2.25 (2H, m). 175

¹H-NMR (CDCl₃) δ: 8.15-8.11 (2H, m), 7.96-7.95 (1H, m), 7.75-7.74 (2H, m), 7.73-7.69 (4H, m), 7.53-7.49 (1H, m), 7.42-7.37 (1H, m), 4.41 (2H, q, J = 7.1 Hz), 2.85 (1H, s), 1.42 (3H, t, J = 7.2 Hz).

TABLE 1-26 compound No. structural formula NMR 176

¹H-NMR (DMSO-D₆) δ: 7.95-7.23 (9H, m), 7.01-6.92 (1H, m), 4.41-4.36 (0.8H, m), 4.25-4.17 (0.2H, m), 3.66-3.56 (1.2H, m), 3.49-3.38 (0.8H, m), 2.26-2.11 (1H, m), 1.95-1.75 (3H, m). 177

¹H-NMR (DMSO-D₆) δ: 7.95-7.30 (8H, m), 4.45-4.39 (0.7H, m), 4.21-4.13 (0.3H, m), 3.68-3.55 (1.4H, m), 3.49-3.38 (0.6H, m), 2.63-2.62 (2.1H, m), 2.52-2.49 (0.4H, m), 2.40-2.39 (0.5H, m), 2.23-2.11 (1H, m), 1.97-1.74 (3H, m). 178

¹H-NMR (DMSO-D₆) δ: 7.95-7.86 (2H, m), 7.75-7.71 (0.7H, m), 7.69-7.64 (2H, m), 7.57-7.38 (3H, m), 7.31 (0.3H, d, J = 7.4 Hz), 4.98-4.93 (0.7H, m), 4.78-4.69 (0.3H, m), 3.70-3.45 (2H, m), 3.11 (2.1H, s), 2.86 (2.1H, s), 2.67 (0.4H, s), 2.64 (0.4H, s), 2.62 (0.5H, s), 2.58 (0.5H, s), 2.34-2.23 (1H, m), 1.97-1.71 (3H, m). 179

¹H-NMR (DMSO-D₆) δ: 7.96 (1H, d, J = 7.9 Hz), 7.92-7.89 (1H, m), 7.88 (1H, br s), 7.83 (1H, dd, J = 7.9, 1.8 Hz), 7.76-7.73 (2H, m), 7.69-7.65 (1H, m), 7.58-7.51 (3H, m), 7.44-7.39 (1H, m), 7.35 (1H, br s). 180

¹H-NMR (DMSO-D₆) δ: 12.88 (1H, br s), 7.89 (2H, d, J = 7.9 Hz), 7.79-7.75 (1H, m), 7.67-7.64 (1H, m), 7.63-7.58 (2H, m), 7.55-7.46 (3H, m), 7.44-7.38 (2H, m), 7.31 (1H, br s). 181

¹H-NMR (CDCl₃) δ: 7.91-7.90 (1H, m), 7.73-7.66 (4H, m), 7.54 (2H, d, J = 8.1 Hz), 7.51-7.46 (1H, m), 7.38-7.34 (1H, m), 7.28 (2H, d, J = 8.6 Hz), 2.76 (1H, s), 2.41 (3H, s). 182

¹H-NMR (DMSO-D₆) δ: 7.88 (2H, d, J = 7.7 Hz), 7.76 (1H, br s), 7.70 (1H, br s), 7.67-7.64 (1H, m), 7.57 (1H, dd, J = 7.9, 1.6 Hz), 7.55-7.37 (6H, m), 7.34 (1H, br s), 7.29 (1H, s).

TABLE 1-27 compound No. structural formula NMR 183

¹H-NMR (DMSO-D₆) δ: 8.19-8.14 (1H, m), 7.91-7.86 (2H, m), 7.67-7.63 (2H, m), 7.56-7.50 (3H, m), 7.47-7.42 (3H, m), 7.42-7.37 (1H, m), 7.26 (1H, s), 2.59 (3H, d, J = 4.6 Hz). 184

¹H-NMR (DMSO-D₆) δ: 7.92 (1H, d, J = 7.7 Hz), 7.90 (1H, d, J = 7.5 Hz), 7.68-7.64 (1H, m), 7.63 (1H, br s), 7.57-7.45 (5H, m), 7.43-7.39 (1H, m), 7.38-7.36 (1H, m), 7.26 (1H, s), 2.77 (3H, br s), 2.52-2.43 (3H, m). 185

¹H-NMR (DMSO-D₆) δ: 8.71-8.68 (2H, m), 8.34-8.31 (1H, m), 8.06 (1H, d, J = 1.5 Hz), 8.01-8.00 (1H, m), 7.83-7.80 (2H, m), 7.78-7.74 (1H, m), 7.66-7.61 (1H, m), 7.58 (1H, s), 7.57-7.52 (1H, m). 186

¹H-NMR (DMSO-D₆) δ: 7.72-7.68 (2H, m), 7.58-7.55 (1H, m), 7.46-7.42 (1H, m), 7.38-7.33 (2H, m), 7.29-7.25 (1H, m), 7.19-7.17 (1H, m), 7.16 (1H, s), 7.15-7.11 (2H, m), 7.08-7.03 (2H, m), 3.32 (3H, s). 187

¹H-NMR (CDCl₃) δ: 7.69-7.66 (1H, m), 7.62-7.58 (2H, m), 7.49-7.44 (1H, m), 7.40-7.35 (3H, m), 7.34-7.30 (1H, m), 7.18-7.13 (1H, m), 7.09 (1H, dd, J = 8.3, 2.3 Hz), 7.07-7.04 (2H, m), 2.69 (1H, s). 188

¹H-NMR (DMSO-D₆) δ: 8.08-8.05 (2H, m), 8.01-7.99 (1H, m), 7.96-7.89 (3H, m), 7.87-7.83 (2H, m), 7.69-7.66 (1H, m), 7.57-7.52 (1H, m), 7.45-7.40 (1H, m), 7.39 (1H, br s). 189

¹H-NMR (CDCl₃) δ: 7.74-7.68 (4H, m), 7.58-7.54 (1H, m), 7.52-7.47 (2H, m), 7.45-7.33 (4H, m), 4.64 (1H, d, J = 13.2 Hz), 4.60 (1H, d, J = 12.8 Hz), 1.78 (1H, br s).

TABLE 1-28 compound No. structural formula NMR 190

¹H-NMR (DMSO-D₆) δ: 9.39 (1H, br s), 7.92 (1H, d, J = 7.7 Hz), 7.89 (1H, d, J = 7.3 Hz), 7.67-7.64 (2H, m), 7.55-7.50 (2H, m), 7.43-7.30 (5H, m), 7.27 (1H, s), 1.88 (3H, br s). 191

¹H-NMR (DMSO-D₆) δ: 8.54-8.49 (1H, m), 8.00-7.88 (6H, m), 7.83-7.79 (2H, m), 7.69-7.66 (1H, m), 7.57-7.52 (1H, m), 7.45-7.40 (1H, m), 7.37 (1H, s), 2.82 (3H, d, J = 4.6 Hz). 192

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, d, J = 7.9 Hz), 7.93-7.90 (2H, m), 7.87 (1H, dd, J = 7.9, 1.6 Hz), 7.79-7.76 (2H, m), 7.69-7.66 (1H, m), 7.56-7.52 (3H, m), 7.44-7.40 (1H, m), 7.37 (1H, s), 3.06-2.92 (6H, m). 193

¹H-NMR (DMSO-D₆) δ: 7.85-7.82 (2H, m), 7.77-7.75 (1H, m), 7.68 (1H, dd, J = 7.9, 1.6 Hz), 7.65-7.61 (1H, m), 7.52-7.47 (1H, m), 7.43-7.39 (2H, m), 7.38-7.33 (1H, m), 7.25 (1H, s), 6.69-6.65 (2H, m), 5.31 (2H, s). 194

¹H-NMR (CDCl₃) δ: 7.93-7.91 (1H, m), 7.75-7.63 (6H, m), 7.52-7.45 (3H, m), 7.40-7.35 (1H, m), 4.77 (2H, d, J = 5.5 Hz), 2.82 (1H, s), 1.69 (1H, t, J = 6.0 Hz). 195

¹H-NMR (DMSO-D₆) δ: 7.94-7.90 (2H, m), 7.77-7.72 (1H, m), 7.69-7.61 (2H, m), 7.56-7.52 (1H, m), 7.46-7.41 (1H, m), 7.37 (0.5H, s), 7.33 (0.5H, s), 4.83-4.78 (0.5H, m), 4.21-4.12 (0.5H, m), 3.65-3.00 (5H, m), 2.01-1.64 (4H, m). 196

¹H-NMR (DMSO-D₆) δ: 8.50-8.47 (1H, m), 7.88-7.83 (2H, m), 7.73-7.69 (1H, m), 7.60-7.56 (1H, m), 7.52-7.48 (1H, m), 7.42 (1H, s), 2.39 (3H, s).

TABLE 1-29 compound No. structural formula NMR 197

¹H-NMR (DMSO-D₆) δ: 10.07 (1H, br s), 7.92 (1H, d, J = 7.9 Hz), 7.88 (1H, d, J = 7.4 Hz), 7.87-7.85 (1H, m), 7.79 (1H, dd, J = 7.9, 1.6 Hz), 7.74-7.70 (2H, m), 7.68-7.64 (3H, m), 7.54-7.50 (1H, m), 7.42-7.37 (1H, m), 7.32 (1H, s), 2.08 (3H, s). 198

¹H-NMR (DMSO-D₆) δ: 8.53 (1H, d, J = 5.1 Hz), 8.03-7.93 (4H, m), 7.70-7.67 (1H, m), 7.64-7.62 (1H, m), 7.58-7.53 (2H, m), 7.46-7.42 (1H, m), 7.40 (1H, s), 2.56 (3H, s). 199

¹H-NMR (DMSO-D₆) δ: 8.04 (1H, br s), 8.03-7.97 (3H, m), 7.95-7.88 (3H, m), 7.82-7.78 (2H, m), 7.69-7.66 (1H, m), 7.56-7.52 (1H, m), 7.44-7.40 (1H, m), 7.39 (1H, br s), 7.36 (1H, s). 200

¹H-NMR (DMSO-D₆) δ: 7.96-7.92 (2H, m), 7.89-7.86 (1H, m), 7.80-7.76 (1H, m), 7.69-7.65 (1H, m), 7.58-7.53 (1H, m), 7.47-7.43 (1H, m), 7.41 (1H, br s), 4.54-4.38 (2H, m), 4.31-4.22 (1H, m), 4.13-4.05 (1H, m), 3.81-3.73 (1H, m), 3.33-3.27 (2H, m), 3.21-3.16 (2H, m), 1.10-1.01 (6H, m). 201

¹H-NMR (DMSO-D₆) δ: 7.96-7.93 (2H, m), 7.88-7.86 (1H, m), 7.80-7.76 (1H, m), 7.69-7.65 (1H, m), 7.58-7.53 (1H, m), 7.47-7.43 (1H, m), 7.41 (1H, br s), 4.55-4.38 (2H, m), 4.30-4.21 (1H, m), 4.17-4.09 (1H, m), 3.72-3.64 (1H, m), 3.34-3.27 (4H, m), 1.90-1.82 (2H, m), 1.81-1.73 (2H, m). 202

¹H-NMR (DMSO-D₆) δ: 7.97-7.93 (2H, m), 7.89-7.86 (1H, m), 7.80-7.76 (1H, m), 7.69-7.66 (1H, m), 7.58-7.53 (1H, m), 7.47-7.43 (1H, m), 7.42 (1H, br s), 4.55-4.41 (2H, m), 4.31-4.23 (1H, m), 4.17-4.07 (1H, m), 3.81-3.72 (1H, m), 3.48-3.43 (2H, m), 3.25-3.20 (2H, m), 1.61-1.54 (2H, m), 1.50-1.41 (4H, m).

TABLE 1-30 compound No. structural formula NMR 203

¹H-NMR (DMSO-D₆) δ: 7.96-7.93 (2H, m), 7.88-7.86 (1H, m), 7.80-7.76 (1H, m), 7.69-7.65 (1H, m), 7.58-7.53 (1H, m), 7.48-7.43 (1H, m), 7.42 (1H, br s), 4.74 (1H, d, J = 3.9 Hz), 4.55-4.39 (2H, m), 4.32-4.23 (1H, m), 4.16-4.07 (1H, m), 3.94-3.86 (1H, m), 3.82-3.74 (1H, m), 3.73-3.65 (1H, m), 3.49-3.41 (1H, m), 3.12-3.01 (2H, m), 1.76-1.66 (2H, m), 1.36-1.22 (2H, m). 204

¹H-NMR (DMSO-D₆) δ: 8.61 (1H, d, J = 4.6 Hz), 8.39 (1H, d, J = 5.1 Hz), 7.75 (1H, d, J = 6.8 Hz), 7.67 (1H, d, J = 7.3 Hz), 7.56-7.44 (2H, m), 7.38-7.28 (3H, m), 7.26-7.19 (1H, m), 6.38-6.29 (1H, m), 2.07-1.99 (3H, m). 205

¹H-NMR (CDCl₃) δ: 7.88-7.85 (1H, m), 7.73-7.63 (4H, m), 7.55-7.51 (2H, m), 7.51-7.46 (1H, m), 7.38-7.34 (1H, m), 6.95-6.91 (2H, m), 4.82 (1H, s), 2.74 (1H, s). 206

¹H-NMR (DMSO-D₆) δ: 7.95-7.91 (2H, m), 7.75-7.73 (1H, m), 7.70-7.65 (2H, m), 7.57-7.52 (1H, m), 7.46-7.41 (1H, m), 7.41-7.37 (1H, m), 3.79-3.47 (7H, m), 3.30-3.18 (1H, m), 2.26-2.00 (2H, m). 207

¹H-NMR (DMSO-D₆) δ: 7.70-7.66 (2H, m), 7.58-7.54 (1H, m), 7.45-7.40 (1H, m), 7.28-7.23 (1H, m), 7.21-7.19 (1H, m), 7.15 (1H, s), 7.07 (1H, dd, J = 8.6, 2.3 Hz), 3.67-3.56 (4H, m), 3.27-3.13 (4H, m), 2.37 (2H, q, J = 7.4 Hz), 1.02 (3H, t, J = 7.4 Hz). 208

¹H-NMR (DMSO-D₆) δ: 7.71-7.67 (2H, m), 7.58-7.55 (1H, m), 7.45-7.40 (1H, m), 7.28-7.23 (1H, m), 7.22-7.20 (1H, m), 7.15 (1H, s), 7.08 (1H, dd, J = 8.5, 2.2 Hz), 3.74-3.58 (4H, m), 3.27-3.13 (4H, m), 2.96-2.88 (1H, m), 1.04 (3H, s), 1.02 (3H, s). 209

¹H-NMR (DMSO-D₆) δ: 7.71-7.66 (2H, m), 7.58-7.54 (1H, m), 7.45-7.41 (1H, m), 7.28-7.23 (1H, m), 7.21-7.19 (1H, m), 7.14 (1H, s), 7.07 (1H, dd, J = 8.3, 2.3 Hz), 3.75-3.69 (4H, m), 3.23-3.16 (4H, m), 1.23 (9H, s).

TABLE 1-31 compound No. structural formula NMR 210

¹H-NMR (DMSO-D₆) δ: 7.71-7.66 (2H, m), 7.58-7.54 (1H, m), 7.45-7.40 (1H, m), 7.28-7.23 (1H, m), 7.21-7.19 (1H, m), 7.15 (1H, s), 7.07 (1H, dd, J = 8.5, 2.2 Hz), 3.64 (3H, s), 3.56-3.51 (4H, m), 3.23-3.18 (4H, m). 211

¹H-NMR (DMSO-D₆) δ: 7.70-7.66 (2H, m), 7.58-7.55 (1H, m), 7.45-7.40 (1H, m), 7.28-7.23 (1H, m), 7.21-7.19 (1H, m), 7.15 (1H, s), 7.07 (1H, dd, J = 8.3, 2.3 Hz), 4.08 (2H, q, J = 7.1 Hz), 3.57-3.50 (4H, m), 3.24-3.17 (4H, m), 1.21 (3H, t, J = 7.1 Hz). 212

¹H-NMR (DMSO-D₆) δ: 7.71-7.66 (2H, m), 7.58-7.55 (1H, m), 7.45-7.40 (1H, m), 7.28-7.23 (1H, m), 7.21-7.19 (1H, m), 7.15 (1H, s), 7.06 (1H, dd, J = 8.3, 2.1 Hz), 4.86-4.74 (1H, m), 3.55-3.49 (4H, m), 3.24-3.15 (4H, m), 1.21 (6H, d, J = 6.3 Hz). 213

¹H-NMR (DMSO-D₆) δ: 8.88 (1H, d, J = 2.0 Hz), 8.17-8.16 (1H, m), 7.97-7.94 (1H, m), 7.78-7.75 (1H, m), 7.68-7.58 (2H, m), 7.64 (1H, s), 4.45-4.35 (2H, m), 4.15-4.06 (2H, m), 2.34-2.26 (2H, m). 214

¹H-NMR (CDCl₃) δ: 7.92-7.85 (3H, m), 7.78-7.65 (5H, m), 7.61-7.56 (1H, m), 7.54-7.49 (1H, m), 7.43-7.38 (1H, m), 2.87 (1H, br s). 215

¹H-NMR (DMSO-D₆) δ: 7.94-7.91 (2H, m), 7.77-7.73 (1H, m), 7.70-7.65 (2H, m), 7.57-7.52 (1H, m), 7.46-7.41 (1H, m), 7.40-7.35 (1H, m), 5.03 (0.5H, d, J = 3.7 Hz), 4.97 (0.5H, d, J = 3.3 Hz), 4.37-4.32 (0.5H, m), 4.29-4.24 (0.5H, m), 3.69-3.50 (2H, m), 3.49-3.20 (2H, m), 2.03-1.76 (2H, m). 216

¹H-NMR (DMSO-D₆) δ: 7.94-7.90 (2H, m), 7.76-7.72 (1H, m), 7.71-7.64 (2H, m), 7.57-7.52 (1H, m), 7.46-7.41 (1H, m), 7.40-7.34 (1H, m), 3.77-3.60 (1H, m), 3.57-3.43 (2H, m), 3.30-3.20 (1H, m), 2.78-2.63 (1H, m), 2.19 (3H, s), 2.10-2.09 (3H, m), 2.07-1.98 (1H, m), 1.81-1.68 (1H, m).

TABLE 1-32 compound No. structural formula NMR 217

¹H-NMR (DMSO-D₆) δ: 12.52 (1H, br s), 7.95-7.91 (2H, m), 7.76-7.73 (1H, m), 7.71-7.64 (2H, m), 7.57-7.52 (1H, m), 7.46-7.41 (1H, m), 7.40-7.35 (1H, m), 3.77-3.47 (4H, m), 3.20-3.05 (1H, m), 2.24-1.96 (2H, m). 218

¹H-NMR (DMSO-D₆) δ: 7.69-7.62 (2H, m), 7.57-7.53 (1H, m), 7.44-7.39 (1H, m), 7.27-7.22 (1H, m), 7.20-7.16 (1H, m), 7.11 (1H, s), 7.06 (1H, dd, J = 8.6, 2.4 Hz), 3.74-3.66 (2H, m), 3.63 (3H, s), 2.90-2.82 (2H, m), 2.61-2.52 (1H, m), 2.00-1.90 (2H, m), 1.74-1.62 (2H, m). 219

¹H-NMR (CDCl₃) δ: 8.37 (1H, dd, J = 8.8, 5.1 Hz), 7.93 (1H, dd, J = 7.8, 1.2 Hz), 7.87-7.84 (1H, m), 7.44-7.37 (2H, m), 7.19-7.13 (1H, m), 4.01 (3H, s), 2.77 (1H, s). 220

¹H-NMR (CDCl₃) δ: 8.12 (1H, dd, J = 10.4, 2.4 Hz), 7.95 (1H, dd, J = 7.9, 1.1 Hz), 7.89-7.86 (1H, m), 7.70-7.65 (1H, m), 7.47-7.41 (1H, m), 7.12-7.07 (1H, m), 4.02 (3H, s), 2.72 (1H, s). 221

¹H-NMR (CDCl₃) δ: 8.36-8.32 (1H, m), 7.94 (1H, dd, J = 8.7, 5.2 Hz), 7.75-7.72 (1H, m), 7.53-7.48 (1H, m), 7.47-7.42 (1H, m), 7.09-7.04 (1H, m), 4.01 (3H, s), 3.21-3.19 (1H, m). 222

¹H-NMR (DMSO-D₆) δ: 7.78-7.71 (2H, m), 7.61-7.57 (1H, m), 7.48-7.43 (2H, m), 7.34-7.25 (2H, m), 3.72-3.63 (2H, m), 3.08 (2H, br s), 2.57-2.46 (1H, m), 2.04-1.96 (2H, m), 1.89-1.72 (2H, m). 223

¹H-NMR (DMSO-D₆) δ: 7.68-7.63 (2H, m), 7.57-7.53 (1H, m), 7.44-7.39 (1H, m), 7.26-7.22 (1H, m), 7.19-7.17 (1H, m), 7.11 (1H, s), 7.06 (1H, dd, J = 8.5, 2.3 Hz), 4.09 (2H, q, J = 7.1 Hz), 3.74-3.66 (2H, m), 2.90-2.82 (2H, m), 2.58-2.48 (1H, m), 1.98-1.90 (2H, m), 1.73-1.62 (2H, m), 1.20 (3H, t, J = 7.1 Hz).

TABLE 1-33 compound No. structural formula NMR 224

¹H-NMR (CDCl₃) δ: 7.93-7.91 (1H, m), 7.79-7.70 (8H, m), 7.54-7.50 (1H, m), 7.43-7.39 (1H, m), 2.81 (1H, br s). 225

¹H-NMR (DMSO-D₆) δ: 7.92 (2H, d, J = 7.7 Hz), 7.75-7.72 (1H, m), 7.69-7.65 (2H, m), 7.57-7.52 (1H, m), 7.46-7.41 (1H, m), 7.40-7.35 (1H, m), 4.75-4.63 (1H, m), 3.64-3.21 (6H, m), 2.42-2.24 (1H, m), 2.00-1.85 (1H, m), 1.72-1.59 (1H, m). 226

¹H-NMR (DMSO-D₆) δ: 7.92 (2H, d, J = 7.4 Hz), 7.76-7.73 (1H, m), 7.70-7.64 (2H, m), 7.56-7.36 (4H, m), 7.00-6.91 (1H, m), 3.75-3.43 (4H, m), 3.04-2.90 (1H, m), 2.17-1.91 (2H, m). 227

¹H-NMR (DMSO-D₆) δ: 8.01-7.96 (0.5H, m), 7.92 (2H, d, J = 7.7 Hz), 7.90-7.85 (0.5H, m), 7.75-7.72 (1H, m), 7.70-7.64 (2H, m), 7.57-7.52 (1H, m), 7.46-7.35 (2H, m), 3.73-3.43 (4H, m), 3.03-2.88 (1H, m), 2.62 (1.5H, d, J = 4.4 Hz), 2.55 (1.5H, d, J = 4.4 Hz), 2.16-1.91 (2H, m). 228

¹H-NMR (DMSO-D₆) δ: 7.94-7.90 (2H, m), 7.75-7.72 (1H, m), 7.69-7.64 (2H, m), 7.57-7.52 (1H, m), 7.46-7.41 (1H, m), 7.38-7.36 (1H, m), 3.62-3.37 (3H, m), 3.24-3.08 (2H, m), 2.30 (1.4H, s), 2.18 (1.6H, d, J = 4.9 Hz), 2.05-1.87 (1H, m), 1.79-1.68 (1H, m). 229

¹H-NMR (DMSO-D₆) δ: 7.94-7.91 (2H, m), 7.76-7.72 (1H, m), 7.71-7.64 (2H, m), 7.57-7.52 (1H, m), 7.46-7.36 (2H, m), 3.77-3.40 (5H, m), 3.07 (1.5H, s), 2.98 (1.5H, s), 2.86 (1.5H, s), 2.80 (1.5H, s), 2.22-2.03 (1H, m), 2.01-1.89 (1H, m). 230

¹H-NMR (DMSO-D₆) δ: 7.66 (1H, d, J = 7.3 Hz), 7.64 (1H, d, J = 8.6 Hz), 7.57-7.53 (1H, m), 7.44-7.39 (1H, m), 7.29 (1H, s), 7.26-7.21 (1H, m), 7.19-7.16 (1H, m), 7.11 (1H, s), 7.05 (1H, dd, J = 8.5, 2.3 Hz), 6.77 (1H, br s), 3.81-3.73 (2H, m), 2.81-2.73 (2H, m), 2.33-2.24 (1H, m), 1.84-1.77 (2H, m), 1.71-1.60 (2H, m).

TABLE 1-34 compound No. structural formula NMR 231

¹H-NMR (DMSO-D₆) δ: 7.77-7.72 (1H, m), 7.68-7.62 (2H, m), 7.57-7.53 (1H, m), 7.44-7.39 (1H, m), 7.26-7.21 (1H, m), 7.19-7.16 (1H, m), 7.11 (1H, s), 7.05 (1H, dd, J = 8.6, 2.4 Hz), 3.82-3.73 (2H, m), 2.81-2.72 (2H, m), 2.58 (3H, d, J = 4.6 Hz), 2.34-2.24 (1H, m), 1.81-1.74 (2H, m), 1.73-1.61 (2H, m). 232

¹H-NMR (DMSO-D₆) δ: 7.68-7.62 (2H, m), 7.57-7.53 (1H, m), 7.45-7.39 (1H, m), 7.27-7.21 (1H, m), 7.19-7.16 (1H, m), 7.11 (1H, s), 7.05 (1H, dd, J = 8.4, 2.2 Hz), 3.83-3.74 (2H, m), 3.06 (3H, s), 2.90-2.78 (3H, m), 2.82 (3H, s), 1.77-1.60 (4H, m). 233

¹H-NMR (DMSO-D₆) δ: 8.33-8.30 (1H, m), 8.11-8.07 (2H, m), 7.99 (1H, d, J = 1.5 Hz), 7.97-7.92 (3H, m), 7.77-7.74 (1H, m), 7.65-7.60 (1H, m), 7.58 (1H, s), 7.56-7.51 (1H, m), 4.36 (2H, q, J = 7.1 Hz), 1.36 (3H, t, J = 7.2 Hz). 234

¹H-NMR (DMSO-D₆) δ: 13.08 (1H, br s), 8.32-8.29 (1H, m), 8.09-8.05 (2H, m), 7.98 (1H, d, J = 1.5 Hz), 7.96-7.94 (1H, m), 7.92-7.88 (2H, m), 7.77-7.73 (1H, m), 7.65-7.60 (1H, m), 7.59-7.50 (2H, m). 235

¹H-NMR (DMSO-D₆) δ: 7.92 (1H, s), 7.88-7.85 (1H, m), 7.73-7.70 (1H, m), 7.63-7.59 (1H, m), 7.58-7.53 (1H, m), 7.45 (1H, s), 4.08 (3H, s), 4.06-3.95 (4H, m), 2.30-2.20 (2H, m). 236

¹H-NMR (DMSO-D₆) δ: 8.01 (1H, d, J = 7.9 Hz), 7.99-7.92 (5H, m), 7.83 (1H, dd, J = 8.1, 1.6 Hz), 7.70-7.67 (1H, m), 7.58-7.53 (1H, m), 7.46-7.42 (1H, m), 7.40 (1H, s), 3.90 (3H, s). 237

¹H-NMR (DMSO-D₆) δ: 7.87-7.83 (2H, m), 7.65-7.61 (1H, m), 7.53-7.49 (1H, m), 7.40-7.33 (2H, m), 7.34 (1H, s), 7.26 (1H, dd, J = 8.2, 2.2 Hz), 3.07 (3H, s), 2.93 (3H, s).

TABLE 1-35 compound No. structural formula NMR 238

¹H-NMR (DMSO-D₆) δ: 13.44 (1H, br s), 8.02-7.99 (1H, m), 7.97-7.92 (4H, m), 7.89-7.86 (1H, m), 7.80- 7.77 (1H, m), 7.70-7.66 (1H, m), 7.57-7.52 (1H, m), 7.46-7.41 (1H, m), 7.39 (1H, br s). 239

¹H-NMR (DMSO-D₆) δ: 7.99 (1H, d, J = 7.9 Hz), 7.95- 7.88 (4H, m), 7.81 (1H, d, J = 1.6 Hz), 7.73 (1H, dd, J = 8.0, 1.5 Hz), 7.69-7.62 (2H, m), 7.59-7.57 (1H, m), 7.55-7.52 (1H, m), 7.45- 7.40 (1H, m), 7.38 (1H, s). 240

¹H-NMR (DMSO-D₆) δ: 8.43- 8.37 (1H, m), 8.01-7.97 (1H, m), 7.96-7.88 (3H, m), 7.83-7.81 (1H, m), 7.75- 7.71 (1H, m), 7.70-7.66 (1H, m), 7.58-7.52 (2H, m), 7.45-7.40 (1H, m), 7.37 (1H, s), 2.79 (3H, d, J = 4.4 Hz). 241

¹H-NMR (DMSO-D₆) δ: 7.99 (1H, d, J = 7.9 Hz), 7.95- 7.90 (3H, m), 7.86 (1H, d, J = 1.6 Hz), 7.76 (1H, dd, J = 8.1, 1.6 Hz), 7.69-7.66 (1H, m), 7.57-7.52 (1H, m), 7.48 (1H, d, J = 7.9 Hz), 7.45-7.40 (1H, m), 7.38 (1H, s), 3.04 (3H, s), 2.84 (3H, s). 242

¹H-NMR (DMSO-D₆) δ: 8.77 (1H, dd, J = 4.9, 1.8 Hz), 8.68 (1H, br s), 7.94 (2H, br s), 7.72-7.68 (1H, m), 7.64-7.59 (1H, m), 7.58 (1H, d, J = 1.5 Hz), 7.48 (1H, s), 7.42-7.37 (1H, m), 7.31-7.26 (1H, m), 6.71 (1H, d, J = 7.5 Hz), 4.42- 4.33 (2H, m), 4.13-4.05 (2H, m), 2.34-2.24 (2H, m). 243

¹H-NMR (DMSO-D₆) δ: 8.78- 8.76 (1H, m), 8.70-8.66 (1H, m), 7.98-7.91 (1H, m), 7.72 (1H, d, J = 1.1 Hz), 7.68 (1H, d, J = 7.5 Hz), 7.63-7.59 (1H, m), 7.54- 7.50 (2H, m), 7.40-7.35 (1H, m), 7.29-7.24 (1H, m), 6.63 (1H, d, J = 7.7 Hz). 244

¹H-NMR (DMSO-D₆) δ: 7.79- 7.76 (1H, m), 7.71 (1H, d, J = 7.9 Hz), 7.62-7.58 (1H, m), 7.49-7.45 (1H, m), 7.36-7.30 (2H, m), 7.19 (1H, dd, J = 7.9, 1.5 Hz), 7.16 (1H, s), 2.06-1.98 (1H, m), 1.04-0.98 (2H, m), 0.75-0.68 (2H, m).

TABLE 1-36 compound No. structural formula NMR 245

¹H-NMR (CDCl₃) δ: 7.98-7.96 (1H, m), 7.93 (1H, s), 7.79-7.76 (1H, m), 7.75- 7.67 (3H, m), 7.53-7.49 (1H, m), 7.42-7.37 (2H, m), 2.96 (1H, br s). 246

¹H-NMR (DMSO-D₆) δ: 7.95- 7.90 (2H, m), 7.80-7.64 (3H, m), 7.57-7.52 (1H, m), 7.46-7.41 (1H, m), 7.39- 7.34 (1H, m), 5.16-4.47 (1H, m), 3.77-3.34 (4H, m), 2.92-2.71 (3H, m), 2.14- 1.91 (5H, m). 247

¹H-NMR (CDCl₃) δ: 8.42 (1H, s), 8.21-8.18 (1H, m), 7.80-7.76 (2H, m), 7.75- 7.72 (1H, m), 7.56-7.52 (1H, m), 7.49-7.44 (1H, m), 3.48 (1H, br s), 2.37 (3H, s). 248

¹H-NMR (CDCl₃) δ: 7.70-7.67 (2H, m), 7.63 (1H, d, J = 7.7 Hz), 7.58 (1H, d, J = 7.9 Hz), 7.48-7.44 (1H, m), 7.43-7.40 (1H, m), 7.36- 7.31 (1H, m), 6.49-6.43 (1H, m), 6.38-6.29 (1H, m), 2.70 (1H, s), 1.92 (3H, d, J = 6.3 Hz). 249

¹H-NMR (CDCl₃) δ: 7.67-7.64 (1H, m), 7.57-7.53 (2H, m), 7.46-7.41 (1H, m), 7.30- 7.23 (2H, m), 7.00-6.96 (1H, m), 4.02 (2H, t, J = 6.4 Hz), 2.70 (1H, s), 1.84-1.76 (2H, m), 1.57- 1.47 (2H, m), 1.02-0.97 (3H, m). 250

¹H-NMR (DMSO-D₆) δ: 7.85 (1H, d, J = 7.7 Hz), 7.73 (1H, d, J = 7.7 Hz), 7.70 (1H, d, J = 7.2 Hz), 7.60- 7.54 (2H, m), 7.45-7.36 (2H, m), 7.37 (1H, s), 4.54 (3H, s). 251

¹H-NMR (DMSO-D₆) δ: 7.93 (1H, d, J = 7.7 Hz), 7.73- 7.68 (2H, m), 7.66-7.61 (1H, m), 7.48 (1H, s), 7.45-7.41 (1H, m), 7.39- 7.34 (1H, m), 6.44 (1H, d, J = 7.4 Hz), 3.92 (3H, s).

TABLE 1-37 compound No. structural formula NMR 252

¹H-NMR (CDCl₃) δ: 7.88-7.86 (1H, m), 7.73-7.69 (1H, m), 7.67-7.58 (3H, m), 7.56- 7.53 (2H, m), 7.50-7.46 (1H, m), 7.41-7.33 (3H, m), 7.30-7.26 (1H, m), 7.20 (1H, d, J = 16.5 Hz), 7.15 (1H, d, J = 16.3 Hz), 2.75 (1H, br s). 253

¹H-NMR (DMSO-D₆) δ: 7.75- 7.72 (2H, m), 7.60-7.57 (1H, m), 7.47-7.43 (1H, m), 7.31-7.27 (1H, m), 7.20 (1H, s), 7.15-7.13 (1H, m), 7.05 (1H, dd, J = 8.4, 2.4 Hz), 3.84 (2H, d, J = 6.2 Hz), 1.86-1.64 (6H, m), 1.32-1.02 (5H, m). 254

¹H-NMR (DMSO-D₆) δ: 7.76- 7.72 (2H, m), 7.60-7.56 (1H, m), 7.47-7.43 (1H, m), 7.31-7.27 (1H, m), 7.20 (1H, s), 7.16-7.14 (1H, m), 7.06 (1H, dd, J = 8.4, 2.4 Hz), 3.91 (2H, d, J = 7.1 Hz), 2.39-2.27 (1H, m), 1.84-1.74 (2H, m), 1.68- 1.50 (4H, m), 1.41-1.31 (2H, m). 255

¹H-NMR (DMSO-D₆) δ: 7.76- 7.72 (2H, m), 7.60-7.56 (1H, m), 7.48-7.43 (1H, m), 7.32-7.27 (1H, m), 7.21 (1H, s), 7.16-7.14 (1H, m), 7.06 (1H, dd, J = 8.4, 2.4 Hz), 4.01 (2H, d, J = 6.6 Hz), 2.78-2.70 (1H, m), 2.14-2.04 (2H, m), 1.97- 1.80 (4H, m). 256

¹H-NMR (DMSO-D₆) δ: 7.76- 7.72 (2H, m), 7.60-7.56 (1H, m), 7.48-7.43 (1H, m), 7.31-7.26 (1H, m), 7.21 (1H, s), 7.15-7.13 (1H, m), 7.05 (1H, dd, J = 8.3, 2.3 Hz), 3.88 (2H, d, J = 7.0 Hz), 1.29-1.19 (1H, m), 0.61-0.56 (2H, m), 0.38- 0.33 (2H, m). 257

¹H-NMR (CDCl₃) δ: 7.67-7.64 (1H, m), 7.57-7.53 (2H, m), 7.46-7.41 (1H, m), 7.30- 7.25 (1H, m), 7.24-7.22 (1H, m), 6.99-6.95 (1H, m), 4.18-4.12 (2H, m), 4.07 (2H, t, J = 6.0 Hz), 2.77 (1H, s), 2.53 (2H, t, J = 7.3 Hz), 2.17-2.10 (2H, m), 1.29-1.24 (3H, m). 258

¹H-NMR (DMSO-D₆) δ: 12.16 (1H, br s), 7.76-7.73 (2H, m), 7.61-7.56 (1H, m), 7.48-7.43 (1H, m), 7.32- 7.27 (1H, m), 7.25-7.21 (1H, m), 7.18-7.14 (1H, m), 7.06 (1H, dd, J = 8.2, 2.0 Hz), 4.05 (2H, t, J = 6.4 Hz), 2.41 (2H, t, J = 7.3 Hz), 2.01-1.93 (2H, m).

TABLE 1-38 compound No. structural formula NMR 259

¹H-NMR (DMSO-D₆) δ: 7.75- 7.71 (2H, m), 7.60-7.56 (1H, m), 7.48-7.43 (1H, m), 7.32-7.27 (1H, m), 7.21 (1H, s), 7.15-7.12 (1H, m), 7.08-7.05 (1H, m), 4.43- 4.37 (1H, m), 2.00-1.91 (2H, m), 1.77-1.68 (2H, m), 1.59-1.22 (6H, m). 260

¹H-NMR (DMSO-D₆) δ: 7.75- 7.71 (2H, m), 7.60-7.56 (1H, m), 7.48-7.43 (1H, m), 7.32-7.27 (1H, m), 7.21 (1H, s), 7.15-7.12 (1H, m), 7.08-7.05 (1H, m), 4.43- 4.37 (1H, m), 2.00-1.91 (2H, m), 1.77-1.68 (2H, m), 1.59-1.22 (6H, m). 261

¹H-NMR (DMSO-D₆) δ: 7.78- 7.74 (2H, m), 7.61-7.56 (2H, m), 7.49-7.44 (1H, m), 7.33-7.28 (1H, m), 7.26- 7.23 (2H, m), 7.23 (1H, s), 7.17 (1H, dd, J = 8.4, 2.4 Hz), 7.05 (1H, dd, J = 5.1, 3.5 Hz), 5.38 (1H, d, J = 12.1 Hz), 5.35 (1H, d, J = 12.1 Hz). 262

¹H-NMR (DMSO-D₆) δ: 7.79- 7.73 (2H, m), 7.61-7.57 (1H, m), 7.51-7.23 (9H, m), 7.16 (1H, dd, J = 8.3, 2.3 Hz), 5.17 (2H, s). 263

¹H-NMR (CDCl₃) δ: 7.72-7.67 (2H, m), 7.48 (1H, s), 7.47 (1H, s), 7.36-7.22 (5H, m), 4.00 (3H, s), 3.20 (1H, br s). 264

¹H-NMR (CDCl₃) δ: 7.67-7.63 (1H, m), 7.57-7.53 (2H, m), 7.45-7.41 (1H, m), 7.29- 7.25 (1H, m), 7.24-7.23 (1H, m), 6.98 (1H, dd, J = 8.3, 2.3 Hz), 3.78 (2H, d, J = 6.6 Hz), 2.66 (1H, s), 2.17-2.05 (1H, m), 1.06 (3H, d, J = 0.9 Hz), 1.04 (3H, d, J = 0.9 Hz). 265

¹H-NMR (CDCl₃) δ: 7.67-7.63 (1H, m), 7.57-7.53 (2H, m), 7.46-7.41 (1H, m), 7.30- 7.23 (2H, m), 6.99 (1H, dd, J = 8.2, 2.4 Hz), 3.98 (2H, t, J = 6.5 Hz), 2.66 (1H, s), 1.89-1.79 (2H, m), 1.06 (3H, t, J = 7.4 Hz).

TABLE 1-39 compound No. structural formula NMR 266

¹H-NMR (CDCl₃) δ: 7.87-7.85 (1H, m), 7.76-7.64 (4H, m), 7.54-7.49 (3H, m), 7.43- 7.36 (2H, m), 2.77 (1H, s). 267

¹H-NMR (DMSO-D₆) δ: 8.17- 8.13 (1H, m), 7.92-7.89 (1H, m), 7.88 (1H, dd, J = 7.9, 1.1 Hz), 7.74-7.71 (1H, m), 7.63-7.58 (1H, m), 7.53-7.45 (2H, m), 7.42 (1H, s), 2.66 (3H, s). 268

¹H-NMR (DMSO-D₆) δ: 8.18 (1H, d, J = 7.7 Hz), 7.70- 7.66 (1H, m), 7.56-7.48 (2H, m), 7.43-7.38 (1H, m), 7.33-7.25 (2H, m), 7.15 (1H, s), 2.37-2.29 (1H, m), 1.17-1.05 (2H, m), 0.85- 0.79 (1H, m), 0.72-0.65 (1H, m). 269

¹H-NMR (CDCl₃) δ: 7.63-7.59 (1H, m), 7.47 (2H, d, J = 8.1 Hz), 7.41-7.36 (1H, m), 7.20-7.16 (1H, m), 6.87- 6.85 (1H, m), 6.58 (1H, dd, J = 8.5, 2.0 Hz), 3.55-3.34 (3H, m), 2.97-2.91 (1H, m), 2.63 (1H, s), 2.48-2.38 (1H, m), 2.20-2.12 (1H, m), 1.71-1.61 (1H, m), 1.15 (3H, d, J = 6.7 Hz). 270

¹H-NMR (DMSO-D₆) δ: 7.76- 7.72 (2H, m), 7.60-7.57 (1H, m), 7.48-7.43 (1H, m) 7.32-7.27 (1H, m), 7.23 (1H, s), 7.16-7.14 (1H, m) 7.06 (1H, dd, J = 8.3, 2.1 Hz), 4.46 (1H, t, J = 5.1 Hz), 4.04 (2H, t, J = 6.5 Hz), 3.50-3.44 (2H, m), 1.82-1.73 (2H, m), 1.63- 1.54 (2H, m). 271

¹H-NMR (DMSO-D₆) δ: 8.07 (1H, d, J = 7.5 Hz), 7.65- 7.61 (1H, m), 7.53-7.47 (1H, m), 7.37-7.33 (1H, m), 7.31 (1H, s), 7.20-7.18 (1H, m), 7.03 (1H, d, J = 2.2 Hz), 3.74-3.68 (4H, m). 3.29-3.24 (4H, m), 1.23 (9H, s). 272

¹H-NMR (CDCl₃) δ: 8.47 (1H, d, J = 7.7 Hz), 7.73-7.70 (1H, m), 7.65 (2H, s), 7.57-7.52 (1H, m), 7.46- 7.42 (1H, m), 2.70 (1H, s).

TABLE 1-40 compound No. structural formula NMR 273

¹H-NMR (DMSO-D₆) δ: 8.53- 8.47 (1H, m), 7.82-7.75 (1H, m), 7.72 (1H, d, J = 7.5 Hz), 7.67 (1H, d, J = 7.5 Hz), 7.50-7.46 (1H, m), 7.46-7.42 (1H, m), 7.36- 7.31 (2H, m), 7.29 (1H, s), 7.28-7.23 (1H, m), 6.76 (1H, d, J = 7.5 Hz), 2.60 (3H, s). 274

¹H-NMR (DMSO-D₆) δ: 7.90- 7.86 (1H, m), 7.79-7.68 (3H, m), 7.59-7.54 (1H, m), 7.48-7.41 (2H, m), 7.39 (1H, s), 2.77 (3H, s). 275

¹H-NMR (DMSO-D₆) δ: 7.77- 7.74 (1H, m), 7.71-7.67 (1H, m), 7.54 (1H, dd, J = 7.7, 1.3 Hz), 7.51-7.47 (1H, m), 7.47-7.39 (2H, m), 7.39 (1H, s), 7.33 (1H, s), 7.25 (1H, dd, J = 6.5, 2.1 Hz), 2.55 (3H, s). 276

¹H-NMR (CDCl₃) δ: 7.68-7.64 (1H, m), 7.57-7.53 (2H, m), 7.46-7.41 (1H, m), 7.30- 7.23 (2H, m), 7.00-6.97 (1H, m), 4.07-4.02 (2H, m), 2.69 (1H, s), 1.92-1.81 (1H, m), 1.74-1.68 (2H, m), 1.00-0.96 (6H, m). 277

¹H-NMR (DMSO-D₆) δ: 13.15 (1H, br s), 7.99 (1H, br s), 7.70-7.58 (3H, m), 7.41-7.27 (4H, m), 7.25- 7.20 (2H, m). 278

¹H-NMR (CDCl₃) δ: 7.68-7.64 (1H, m), 7.57-7.53 (2H, m), 7.46-7.40 (1H, m), 7.30- 7.23 (2H, m), 7.00-6.97 (1H, m), 4.04-3.99 (2H, m), 2.69 (1H, br s), 1.86-1.78 (2H, m), 1.52-1.35 (4H, m), 0.98-0.92 (3H, m). 279

¹H-MMR (CDCl₃) δ: 7.68-7.64 (1H, m), 7.58-7.53 (2H, m), 7.46-7.41 (1H, m), 7.30- 7.24 (2H, m), 7.01-6.98 (1H, m), 3.66 (2H, s), 2.70 (1H, s), 1.07 (9H, s).

TABLE 1-41 compound No. structural formula NMR 280

¹H-NMR (DMSO-D₆) δ: 7.77- 7.72 (2H, m), 7.61-7.57 (1H, m), 7.48-7.43 (1H, m), 7.33 (1H, br s), 7.32-7.27 (1H, m), 7.25-7.22 (1H, m), 7.16-7.14 (1H, m), 7.08- 7.04 (1H, m), 6.78 (1H, br s), 4.03 (2H, t, J = 6.3 Hz), 2.25 (2H, t, J = 7.2 Hz), 1.99-1.91 (2H, m). 281

¹H-NMR (DMSO-D₆) δ: 7.79 (1H, br s), 7.77-7.72 (2H, m), 7.61-7.57 (1H, m), 7.48-7.43 (1H, m), 7.32- 7.27 (1H, m), 7.25-7.22 (1H, m), 7.16-7.13 (1H, m), 7.08-7.04 (1H, m), 4.05- 3.99 (2H, m), 2.60-2.56 (3H, m), 2.28-2.23 (2H, m), 2.01-1.92 (2H, m). 282

¹H-NMR (DMSO-D₆) δ: 7.77- 7.72 (2H, m), 7.61-7.57 (1H, m), 7.48-7.43 (1H, m), 7.32-7.27 (1H, m), 7.24- 7.22 (1H, m), 7.17-7.14 (1H, m), 7.09-7.05 (1H, m), 4.06 (2H, t, J = 6.4 Hz), 2.97 (3H, s), 2.83 (3H, s), 2.50-2.45 (2H, m), 2.00- 1.92 (2H, m). 283

¹H-NMR (CDCl₃) δ: 7.67-7.64 (1H, m), 7.58-7.52 (2H, m), 7.45-7.41 (1H, m), 7.45 (1H, s), 7.30-7.25 (1H, m), 7.25-7.23 (1H, m), 6.97 (1H, dd, J = 8.4, 2.4 Hz), 4.13 (2H, q, J = 7.1 Hz), 4.07-4.01 (2H, m), 2.43- 2.37 (2H, m), 1.92-1.78 (4H, m), 1.26 (3H, t, J = 7.2 Hz). 284

¹H-NMR (DMSO-D₆) δ: 7.77- 7.72 (2H, m), 7.61-7.57 (1H, m), 7.48-7.43 (1H, m), 7.32-7.27 (1H, m), 7.24- 7.22 (1H, m), 7.18-7.14 (1H, m), 7.08-7.05 (1H, m), 4.60-4.56 (1H, m), 4.13- 4.07 (2H, m), 3.61-3.55 (2H, m), 1.94-1.85 (2H, m). 285

¹H-NMR (DMSO-D₆) δ: 8.72 (1H, dd, J = 4.9, 1.5 Hz), 8.64 (1H, d, J = 1.5 Hz), 7.92-7.86 (1H, m), 7.61- 7.55 (2H, m), 7.30-7.27 (1H, m), 7.22 (1H, s), 7.21-7.14 (2H, m), 6.86 (1H, d, J = 2.4 Hz), 6.55 (1H, d, J = 6.8 Hz), 3.75- 3.68 (4H, m), 3.29-3.24 (4H, m), 1.23 (9H, s). 286

¹H-NMR (DMSO-D₆) δ: 8.04 (1H, s), 7.68-7.63 (1H, m) 7.66 (1H, d, J = 0.7 Hz), 7.60-7.57 (1H, m), 7.41 (1H, s), 7.40-7.34 (4H, m) 3.96 (3H, s).

TABLE 1-42 compound No. structural formula NMR 287

¹H-NMR (DMSO-D₆) δ: 13.07 (1H, br s), 7.78-7.73 (2H, m), 7.61-7.56 (1H, m), 7.49-7.43 (1H, m), 7.33- 7.28 (1H, m), 7.27-7.24 (1H, m), 7.15-7.13 (1H, m), 7.06-7.02 (1H, m), 4.75 (2H, s). 288

¹H-NMR (DMSO-D₆) δ: 7.79- 7.74 (2H, m), 7.63 (1H, br s), 7.62-7.58 (1H, m), 7.49-7.44 (1H, m), 7.43 (1H, br s), 7.34-7.29 (1H, m), 7.27-7.22 (2H, m), 7.10-7.06 (1H, m), 4.49 (2H, s). 289

¹H-NMR (DMSO-D₆) δ: 8.17- 8.11 (1H, m), 7.80-7.74 (2H, m), 7.62-7.58 (1H, m), 7.49-7.45 (1H, m), 7.34- 7.28 (1H, m), 7.27-7.24 (2H, m), 7.11-7.07 (1H, m), 4.53 (2H, s), 2.70-2.65 (3H, m). 290

¹H-NMR (DMSO-D₆) δ: 7.77- 7.72 (2H, m), 7.61-7.57 (1H, m), 7.49-7.44 (1H, m), 7.33-7.28 (1H, m), 7.26- 7.23 (1H, m), 7.17-7.14 (1H, m), 7.06-7.01 (1H, m), 4.88 (2H, s), 3.02 (3H, s), 2.86 (3H, s). 291

¹H-NMR (DMSO-D₆) δ: 12.40 (1H, br s), 7.80-7.71 (2H, m), 7.62-7.56 (1H, m), 7.49-7.42 (1H, m), 7.34- 7.21 (2H, m), 7.15 (1H, s), 7.11-7.04 (1H, m), 4.28- 4.18 (2H, m), 2.77-2.69 (2H, m). 292

¹H-NMR (DMSO-D₆) δ: 7.78- 7.72 (2H, m), 7.61-7.57 (1H, m), 7.48-7.43 (1H, m), 7.32-7.27 (1H, m), 7.23 (1H, s), 7.18-7.16 (1H, m), 7.07 (1H, dd, J = 8.4, 2.4 Hz), 4.89 (1H, t, J = 5.5 Hz), 4.07-4.03 (2H, m), 3.77-3.72 (2H, m). 293

¹H-HMR (DMSO-D₆) δ: 7.60- 7.56 (2H, m), 7.54-7.50 (1H, m), 7.40-7.36 (1H, m), 7.20-7.15 (1H, m), 7.08- 7.05 (1H, m), 6.83-6.80 (1H, m), 6.65-6.61 (1H, m), 3.98-3.88 (1H, m), 3.46- 3.39 (1H, m), 3.22-3.13 (1H, m), 2.11-1.94 (3H, m), 1.70 (1H, d, J = 42.9 Hz), 1.15 (3H, t, J = 6.8 Hz).

TABLE 1-43 compound No. structural formula NMR 294

¹H-NMR (CDCl₃) δ: 7.67-7.63 (1H, m), 7.57-7.52 (2H, m), 7.46-7.41 (1H, m), 7.30- 7.23 (2H, m), 7.00-6.96 (1H, m), 4.01 (2H, t, J = 6.5 Hz), 2.70-2.70 (1H, m), 1.84-1.76 (2H, m), 1.53- 1.44 (2H, m), 1.39-1.32, (4H, m), 0.95-0.89 (3H, m). 295

¹H-NMR (DMSO-D₆) δ: 12.05 (1H, br s), 7.77-7.72 (2H, m), 7.60-7.57 (1H, m), 7.48-7.43 (1H, m), 7.32- 7.27 (1H, m), 7.22 (1H, s), 7.16-7.14 (1H, m), 7.08- 7.05 (1H, m), 4.04 (2H, t, J = 5.9 Hz), 2.31 (2H, t, J = 7.2 Hz), 1.80-1.63 (4H, m). 296

¹H-NMR (CDCl₃) δ: 7.67-7.64 (1H, m), 7.58-7.53 (2H, m), 7.46-7.41 (1H, m), 7.30- 7.23 (2H, m), 7.00-6.96 (1H, m), 4.04 (2H, t, J = 6.4 Hz), 3.70 (2H, t, J = 5.8 Hz), 2.79 (1H, s), 1.89-1.81 (2H, m), 1.71- 1.63 (2H, m), 1.62-1.53 (2H, m), 1.32-1.20 (1H, m). 297

¹H-NMR (DMSO-D₆) δ: 7.94- 7.88 (2H, m), 7.68-7.61 (2H, m), 7.58-7.51 (2H, m), 7.45-7.40 (1H, m), 7.35 (1H, br s), 4.81 (1H, t, J = 5.4 Hz), 3.68-3.45 (4H, m), 3.00 (3H, br s). 298

¹H-NMR (CDCl₃) δ: 7.67-7.64 (1H, m), 7.57-7.53 (2H, m), 7.46-7.41 (1H, m), 7.30- 7.23 (2H, m), 6.98 (1H, dd, J = 8.4, 2.4 Hz), 4.03 (2H, t, J = 6.4 Hz), 3.67 (2H, t, J = 6.4 Hz), 2.81 (1H, s), 1.87-1.79 (2H, m), 1.66-1.58 (2H, m), 1.52- 1.41 (4H, m), 1.29-1.20 (1H, m). 299

¹H-NMR (DMSO-D₆) δ: 7.76- 7.72 (2H, m), 7.60-7.57 (1H, m), 7.48-7.43 (1H, m), 7.32-7.27 (1H, m), 7.21 (1H, s), 7.16-7.14 (1H, m), 7.06 (1H, dd, J = 8.4, 2.4 Hz), 4.04 (2H, t, J = 6.3 Hz), 2.96 (3H, s), 2.81 (3H, s), 2.37 (2H, t, J = 7.3 Hz), 1.80-1.72 (2H, m), 1.70-1.62 (2H, m). 300

¹H-NMR (DMSO-D₆) δ: 9.38 (1H, s), 8.96 (2H, br s), 7.81-7.77 (1H, m), 7.71- 7.67 (1H, m), 7.56-7.52 (1H, m), 7.45 (1H, dd, J = 7.7, 1.1 Hz), 7.40-7.35 (1H, m), 7.37 (1H, s), 7.31-7.26 (1H, m), 6.71 (1H, d, J = 7.7 Hz).

TABLE 1-44 compound No. structural formula NMR 301

¹H-NMR (DMSO-D₆) δ: 7.78-7.72 (2H, m), 7.61-7.57 (1H, m), 7.50-7.43 (2H, m), 7.33-7.27 (1H, m), 7.25- 7.23 (1H, m), 7.16-7.13 (1H, m), 7.08-7.04 (1H, m), 6.95 (1H, br s), 4.25-4.20 (2H, m), 2.59-2.53 (2H, m). 302

¹H-NMR (DMSO-D₆) δ: 7.98-7.91 (1H, m), 7.77-7.72 (2H, m), 7.61-7.57 (1H, m), 7.49-7.43 (1H, m), 7.33- 7.27 (1H, m), 7.25-7.23 (1H, m), 7.15-7.12 (1H, m), 7.08-7.04 (1H, m), 4.24 (2H, t, J = 5.3 Hz), 2.63- 2.60 (3H, m), 2.59-2.54 (2H, m). 303

¹H-NMR (DMSO-D₆) δ: 7.77-7.72 (2H, m), 7.60-7.57 (1H, m), 7.48-7.43 (1H, m), 7.32-7.27 (1H, m), 7.24 (1H, s), 7.16-7.14 (1H, m), 7.08-7.04 (1H, m), 4.25 (2H, t, J = 6.3 Hz), 3.01 (3H, s), 2.85 (3H, s), 2.82 (2H, t, J = 6.3 Hz). 304

¹H-NMR (CDCl₃) δ: 8.03- 7.87 (1H, m), 7.84-7.64 (4H, m), 7.54-7.48 (1H, m), 7.45- 7.39 (1H, m), 5.01-4.86 (1H, m), 4.59-4.09 (1H, m), 3.88- 3.47 (4H, m), 2.77-2.61 (1H, m), 2.44-2.21 (1H, m). 305

¹H-NMR (DMSO-D₆) δ: 7.79-7.71 (3H, m), 7.61-7.57 (1H, m), 7.49-7.43 (1H, m), 7.33-7.27 (1H, m), 7.24- 7.22 (1H, m), 7.17-7.14 (1H, m), 7.09-7.04 (1H, m), 4.06-4.00 (2H, m), 2.59- 2.55 (3H, m), 2.16-2.11 (2H, m), 1.76-1.62 (4H, m). 306

¹H-NMR (DMSO-D₆) δ: 7.77-7.72 (2H, m), 7.61- 7.57 (1H, m), 7.49-7.43 (1H, m), 7.33-7.26 (2H, m), 7.24-7.22 (1H, m), 7.17-7.14 (1H, m), 7.09-7.04 (1H, m), 6.73 (1H, br s), 4.06-4.01 (2H, m), 2.16-2.10 (2H, m), 1.78-1.63 (4H, m). 307

¹H-NMR (DMSO-D₆) δ: 7.94-7.90 (2H, m), 7.68- 7.64 (1H, m), 7.60-7.47 (3H, m), 7.45-7.40 (1H, m), 7.36 (1H, s), 3.50-3.35 (1H, m), 3.26-3.09 (1H, m), 3.01-2.88 (3H, m), 1.71-1.47 (2H, m), 1.00-0.59 (3H, m).

TABLE 1-45 compound No. structural formula NMR 308

¹H-NMR (DMSO-D₆) δ: 7.94-7.90 (2H, m), 7.68-7.64 (1H, m), 7.60-7.49 (3H, m), 7.45-7.40 (1H, m), 7.36 (1H, s), 3.53-3.11 (2H, m), 3.01- 2.89 (3H, m), 1.65-0.68 (7H, m). 309

¹H-NMR (DMSO-D₆) δ: 7.78 (1H, dd, J = 4.9, 3.1 Hz), 7.70-7.64 (2H, m), 7.65 (1H, dd, J = 4.2, 2.1 Hz), 7.43 (1H, t, J = 7.5 Hz), 7.37-7.21 (4H, m), 7.26 (1H, s), 6.89 (1H, d, J = 7.3 Hz). 310

¹H-NMR (DMSO-D₆) δ: 8.62- 8.57 (1H, m), 8.17-8.14 (1H, m), 8.06-8.01 (1H, m), 7.97- 7.92 (2H, m), 7.70-7.66 (1H, m), 7.58-7.52 (1H, m), 7.48- 7.43 (1H, m), 7.37-7.34 (1H, m), 4.78-4.72 (1H, m), 3.58- 3.49 (2H, m), 3.43-3.27 (2H, m). 311

¹H-NMR (DMSO-D₆) δ: 8.63- 8.57 (1H, m), 8.16-8.11 (1H, m), 8.04-7.99 (1H, m), 7.97- 7.91 (2H, m), 7.58-7.52 (1H, m), 7.48-7.42 (1H, m), 7.37- 7.33 (1H, m), 4.51-4.47 (1H, m), 3.52-3.45 (2H, m), 3.39- 3.27 (2H, m), 1.75-1.67 (2H, m). 312

¹H-NMR (DMSO-D₆) δ: 8.62 (1H, t, J = 5.1 Hz), 8.16-8.13 (1H, m), 8.04-8.00 (1H, m), 7.96-7.91 (2H, m), 7.70-7.65 (1H, m), 7.57-7.53 (1H, m), 7.47-7.42 (1H, m), 7.37-7.35 (1H, m), 4.44-4.40 (1H, m), 3.46-3.40 (2H, m), 3.35-3.24 (2H, m), 1.62-1.53 (2H, m), 1.52-1.44 (2H, m). 313

¹H-NMR (CD₃OD) δ: 7.81 (1H, d, J = 7.1 Hz), 7.69 (1H, d, J = 7.3 Hz), 7.57 (1H, d, J = 7.5 Hz), 7.49-7.43 (1H, m), 7.37-7.27 (3H, m), 2.56 (3H, s). 314

¹H-NMR (DMSO-D₆) δ: 12.86 (1H, br s), 7.99-7.76 (4H, m), 7.67 (1H, d, J = 7.1 Hz), 7.58-7.52 (1H, m), 7.48- 7.35 (2H, m), 5.20-5.04 (0.3H, m), 4.81-4.72 (0.7H, m), 4.47-3.91 (2H, m), 2.81-2.57 (1H, m), 2.29-2.05 (1H, m).

TABLE 1-46 compound No. structural formula NMR 315

¹H-NMR (DMSO-D₆) δ: 8.62 (1H, t, J = 5.6 Hz), 8.15-8.13 (1H, m), 8.01 (1H, dd, J = 7.9, 1.8 Hz), 7.96-7.91 (2H, m), 7.69-7.66 (1H, m), 7.57-7.52 (1H, m), 7.46-7.42 (1H, m), 7.34 (1H, s), 3.36-3.27 (2H, m), 1.15 (3H, t, J = 7.2 Hz). 316

¹H-NMR (DMSO-D₆) δ: 8.60 (1H, t, J = 5.5 Hz), 8.15-8.13 (1H, m), 8.02 (1H, dd, J = 7.9, 1.5 Hz), 7.96-7.91 (2H, m), 7.69- 7.66 (1H, m), 7.57-7.52 (1H, m), 7.46-7.42 (1H, m), 7.34 (1H, s), 3.28-3.21 (2H, m), 1.61-1.51 (2H, m), 0.91 (3H, t, J = 7.5 Hz). 317

¹H-NMR (DMSO-D₆) δ: 7.80- 7.78 (1H, m), 7.76 (1H, d, J = 7.7 Hz), 7.62-7.59 (1H, m), 7.52-7.45 (2H, m), 7.40- 7.26 (6H, m), 7.23-7.17 (1H, m), 7.18 (1H, s), 4.03 (2H, s). 318

¹H-NMR (DMSO-D₆) δ: 11.99 (1H, br s), 7.76-7.72 (2H, m), 7.60-7.56 (1H, m), 7.47-7.43 (1H, m), 7.31-7.27 (1H, m), 7.21 (1H, s), 7.15-7.13 (1H, m), 7.06 (1H, dd, J = 8.4, 2.4 Hz), 4.02 (2H, t, J = 6.6 Hz), 2.24 (2H, t, J = 7.3 Hz), 1.78- 1.70 (2H, m), 1.62-1.53 (2H, m), 1.49-1.42 (2H, m). 319

¹H-NMR (DMSO-D₆) δ: 7.94- 7.90 (2H, m), 7.68-7.64 (1H, m), 7.60-7.48 (3H, m), 7.45- 7.41 (1H, m), 7.37 (1H, s), 4.46-4.34 (1H, m), 3.53-3.14 (4H, m), 3.01-2.86 (3H, m), 1.69-1.13 (4H, m). 320

¹H-NMR (DMSO-D₆) δ: 8.13 (3H, br s), 7.80 (1H, d, J = 8.3 Hz), 7.77 (1H, d, J = 7.4 Hz), 7.62-7.59 (1H, m), 7.50- 7.45 (1H, m), 7.34-7.30 (1H, m), 7.24-7.22 (1H, m), 7.13 (1H, dd, J = 8.5, 2.4 Hz), 4.24 (2H, t, J = 5.1 Hz), 3.57 (1H, s), 3.25 (2H, br s). 321

¹H-NMR (DMSO-D₆) δ: 8.91 (2H, br s), 7.81 (1H, d, J = 8.3 Hz), 7.79-7.76 (1H, m), 7.63- 7.59 (1H, m), 7.50-7.45 (1H, m), 7.34-7.30 (1H, m), 7.24-7.23 (1H, m), 7.24-7.23 (1H, m), 7.14 (1H, dd, J = 8.3, 2.3 Hz), 4.31 (2H, t, J = 5.1 Hz), 3.39-3.34 (2H, m), 2.65 (3H, br s).

TABLE 1-47 compound No. structural formula NMR 322

¹H-NMR (DMSO-D₆) δ: 7.76- 7.73 (2H, m), 7.61-7.56 (1H, m), 7.48-7.43 (1H, m), 7.32- 7.27 (1H, m), 7.21 (1H, s), 7.17-7.15 (1H, m), 7.08 (1H, dd, J = 8.4, 2.4 Hz), 4.11 (2H, t, J = 5.7 Hz), 2.64 (2H, t, J = 5.7 Hz), 2.23 (6H, s). 323

¹H-NMR (CDCl₃) δ: 7.68- 7.64 (1H, m), 7.58-7.54 (2H, m), 7.47-7.42 (1H, m), 7.31-7.23 (2H, m), 6.98 (1H, dd, J = 8.3, 2.6 Hz), 5.00 (1H, br s), 4.08 (2H, t, J = 5.1 Hz), 3.59-3.52 (2H, m), 2.87 (1H, br s), 1.46 (9H, s). 324

¹H-NMR (CDCl₃) δ: 7.68-7.65 (1H, m), 7.58-7.54 (2H, m), 7.46-7.42 (1H, m), 7.31-7.21 (2H, m), 6.98 (1H, dd, J = 8.3, 2.3 Hz), 4.15 (2H, br s), 3.65- 3.59 (2H, m), 2.99 (3H, br s), 2.96-2.90 (1H, m), 1.46 (9H, s). 325

¹H-NMR (CDCl₃) δ: 7.68-7.65 (1H, m), 7.58-7.55 (2H, m), 7.47-7.42 (1H, m), 7.32-7.27 (1H, m), 7.27-7.24 (1H, m), 6.98 (1H, dd, J = 8.3, 2.3 Hz), 5.94 (1H, br s), 4.09 (2H, t, J = 5.0 Hz), 3.70-3.65 (2H, m), 3.03 (1H, br s), 2.01 (3H, s). 326

¹H-NMR (CDCl₃) δ: 7.69-7.65 (1H, m), 7.58-7.53 (2H, m), 7.47-7.41 (1H, m), 7.32-7.21 (2H, m), 6.97 (1H, dd, J = 8.3, 2.6 Hz), 4.19-4.15 (2H, m), 3.80-3.68 (2H, m), 3.26 (0.7H, s), 3.22 (0.3H, s), 3.17 (2.1H, s), 3.00 (0.9H, s), 2.18 (0.9H, s), 2.08 (2.1H, s). 327

¹H-NMR (DMSO-D₆) δ: 7.92 (2H, d, J = 7.5 Hz), 7.68-7.65 (1H, m), 7.62-7.49 (3H, m), 7.45-7.41 (1H, m), 7.38 (1H, s), 4.55-4.38 (1H, m), 3.57-3.21 (4H, m), 3.01-2.91 (3H, m), 1.81-1.63 (2H, m). 328

¹H-NMR (DMSO-D₆) δ: 8.32 (1H, d, J = 7.5 Hz), 7.83 (1H, s), 7.79 (1H, s), 7.77-7.73 (1H, m), 7.66-7.61 (1H, m), 7.59-7.52 (2H, m), 4.67 (1H, t, J = 5.4 Hz), 4.56-4.45 (1H, m), 4.42-4.36 (1H, m), 4.33-4.15 (2H, m), 3.94-3.86 (1H, m), 3.54-3.48 (2H, m), 3.46-3.40 (2H, m).

TABLE 1-48 compound No. structural formula NMR 329

¹H-NMR (DMSO-D₆) δ: 8.32 (1H, d, J = 7.5 Hz), 7.83 (1H, s), 7.79-7.73 (2H, m), 7.66- 7.53 (3H, m), 4.58-4.41 (2H, m), 4.32-4.23 (1H, m), 4.18- 4.10 (1H, m), 3.83-3.74 (1H, m), 2.86 (3H, s), 2.86 (3H, s). 330

¹H-NMR (DMSO-D₆) δ: 8.32 (1H, d, J = 7.7 Hz), 7.83 (1H, s), 7.79-7.73 (2H, m), 7.66- 7.61 (1H, m), 7.59-7.52 (1H, m), 7.58 (1H, s), 4.83 (1H, t, J = 5.3 Hz), 4.41-4.32 (1H, m), 4.12-4.03 (2H, m), 3.85- 3.78 (1H, m), 3.56 (2H, t, J = 5.7 Hz), 2.80-2.69 (1H, m). 331

¹H-NMR (DMSO-D₆) δ: 7.76- 7.72 (2H, m), 7.60-7.56 (1H, m), 7.48-7.42 (1H, m), 7.32- 7.26 (1H, m), 7.22 (1H, s), 7.17-7.14 (1H, m), 7.06 (1H, dd, J = 8.5, 2.4 Hz), 4.09 (2H, t, J = 6.4 Hz), 2.71 (2H, t, J = 6.8 Hz), 1.86-1.75 (2H, m). 332

¹H-NMR (DMSO-D₆) δ: 8.74 (1H, br s), 7.79-7.74 (2H, m), 7.62-7.58 (1H, m), 7.49-7.44 (1H, m), 7.33-7.28 (1H, m), 7.25 (1H, s), 7.19-7.17 (1H, m), 7.08 (1H, dd, J = 8.3, 2.6 Hz), 4.13 (2H, t, J = 6.0 Hz), 3.08 (2H, br s), 2.58 (3H, br s), 2.14-2.06 (2H, m). 333

¹H-NMR (CDCl₃) δ: 7.71-7.67 (1H, m), 7.55 (2H, d, J = 8.3 Hz), 7.44-7.38 (1H, m), 7.30- 7.23 (2H, m), 6.95 (1H, dd, J = 8.3, 2.3 Hz), 3.87-3.80 (2H, m), 2.18-2.11 (2H, m), 1.88 (6H, s), 1.81-1.70 (2H, m). 334

¹H-NMR (CDCl₃) δ: 7.69-7.64 (1H, m), 7.58-7.52 (2H, m), 7.47-7.40 (1H, m), 7.34-7.23 (2H, m), 7.00-6.95 (1H, m), 4.07-4.05 (2H, m), 3.66-3.43 (2H, m), 3.03 (1.7H, s), 2.94 (1.3H, s), 2.10-2.00 (2H, m), 2.08 (1.3H, s), 2.05 (1.8H, s). 335

¹H-NMR (DMSO-D₆) δ: 9.40 (1H, s), 8.99 (2H, br s), 7.78- 7.75 (1H, m), 7.72-7.68 (1H, m), 7.63 (1H, d, J = 2.0 Hz), 7.58 (1H, s), 7.43-7.38 (1H, m), 7.34-7.29 (1H, m), 6.68 (1H, d, J = 7.5 Hz).

TABLE 1-49 compound No. structural formula NMR 336

¹H-NMR (DMSO-D₆) δ: 8.59 (3H, br s), 7.81 (1H, d, J = 7.9 Hz), 7.75-7.67 (2H, m), 7.60- 7.54 (2H, m), 7.50-7.44 (2H, m), 7.34 (1H, s), 4.53 (1H, d, J = 15.0 Hz), 4.46 (1H, d, J = 15.0 Hz). 337

¹H-NMR (DMSO-D₆) δ: 7.94 (2H, d, J = 7.7 Hz), 7.88-7.86 (1H, m), 7.80-7.76 (1H, m), 7.69-7.66 (1H, m), 7.57-7.53 (1H, m), 7.47-7.43 (1H, m), 7.41 (1H, s), 5.02-4.89 (1H, m), 4.55-4.06 (5H, m), 3.75- 3.61 (1H, m), 3.47-3.12 (4H, m), 2.00-1.70 (2H, m). 338

¹H-NMR (DMSO-D₆) δ: 8.56 (1H, t, J = 5.6 Hz), 8.01-7.98 (1H, m), 7.91 (1H, d, J = 7.7 Hz), 7.84-7.82 (1H, m), 7.73- 7.69 (1H, m), 7.59-7.54 (1H, m), 7.48-7.43 (1H, m), 7.27 (1H, s), 4.40 (1H, t, J = 5.1 Hz), 3.46-3.40 (2H, m), 3.30- 3.25 (2H, m), 2.68 (3H, s), 1.61-1.53 (2H, m), 1.51-1.43 (2H, m). 339

¹H-NMR (DMSO-D₆) δ: 8.34- 8.30 (1H, m), 7.83-7.80 (1H, m), 7.77-7.73 (2H, m), 7.65- 7.61 (1H, m), 7.59-7.53 (2H, m), 5.77 (1H, d, J = 6.2 Hz), 4.56-4.42 (2H, m), 4.34-4.24 (1H, m), 4.15-4.02 (1H, m), 3.87-3.77 (1H, m). 340

¹H-NMR (CDCl₃) δ: 7.69-7.64 (1H, m), 7.58-7.54 (2H, m), 7.47-7.41 (1H, m), 7.32- 7.24 (2H, m), 6.98 (1H, dd, J = 8.3, 2.3 Hz), 5.76 (1H, br s), 4.10 (2H, t, J = 5.8 Hz), 3.51-3.42 (2H, m), 3.11 (1H, br s), 2.07-1.96 (2H, m), 1.98 (3H, s). 341

¹H-NMR (DMSO-D₆) δ: 8.78 (1H, dd, J = 4.7, 1.7 Hz), 8.76- 8.74 (1H, m), 8.06-7.99 (4H, m), 7.95-7.91 (2H, m), 7.75 (1H, d, J = 1.8 Hz), 7.37-7.69 (1H, m), 7.63 (1H, dd, J = 7.6, 5.2 Hz), 7.49 (1H, s), 7.41- 7.36 (1H, m), 7.31-7.26 (1H, m), 6.72 (1H, d, J = 7.7 Hz), 1.58 (9H, s). 342

¹H-NMR (DMSO-D₆) δ: 9.00- 8.96 (1H, m), 8.91 (1H, dd, J = 5.2, 1.4 Hz), 8.37-8.32 (1H, m), 8.11-8.05 (3H, m), 7.97-7.92 (2H, m), 7.91-7.86 (1H, m), 7.84-7.81 (1H, m), 7.74-7.70 (1H, m), 7.52 (1H, br s), 7.43-7.38 (1H, m), 7.32- 7.27 (1H, m), 6.79 (1H, d, J = 7.5 Hz).

TABLE 1-50 compound No. structural formula NMR 343

¹H-NMR (DMSO-D₆) δ: 8.15- 8.13 (1H, m), 8.08-8.05 (1H, m), 7.85 (1H, d, J = 1.5 Hz), 7.73-7.68 (1H, m), 7.67 (1H, d, J = 0.9 Hz), 7.49-7.35 (4H, m), 3.97 (3H, s), 3.90 (3H, s). 344

¹H-NMR (DMSO-D₆) δ: 13.24 (1H, br s), 8.14-8.12 (1H, m), 8.06-8.05 (1H, m), 7.83 (1H, d, J = 1.6 Hz), 7.72-7.68 (1H, m), 7.66 (1H, d, J = 0.7 Hz), 7.47-7.36 (4H, m), 3.97 (3H, s). 345

¹H-NMR (DMSO-D₆) δ: 8.62 (1H, t, J = 5.7 Hz), 8.10 (1H, s), 8.02 (1H, s), 7.82 (1H, d, J = 1.5 Hz), 7.72-7.62 (1H, m), 7.65 (1H, s), 7.44-7.30 (3H, m), 7.34 (1H, s), 4.40 (1H, t, J = 5.1 Hz), 3.98 (3H, s), 3.44-3.39 (2H, m), 3.36- 3.19 (2H, m), 1.63-1.39 (4H, m). 346

¹H-NMR (DMSO-D₆) δ: 8.04- 8.00 (1H, m), 7.69-7.63 (2H, m), 7.62-7.58 (1H, m), 7.43- 7.30 (5H, m), 4.82 (1H, t, J = 5.3 Hz), 3.96 (3H, s), 3.68- 3.59 (1H, m), 3.56-3.48 (2H, m), 3.40-3.33 (1H, m), 3.01 (3H, s). 347

¹H-NMR (CDCl₃) δ: 7.72-7.67 (2H, m), 7.52 (1H, s), 7.49 (1H, s), 7.36-7.21 (5H, m), 4.26 (2H, q, J = 7.3 Hz), 3.15 (1H, br s), 1.57 (3H, t, J = 7.3 Hz). 348

¹H-NMR (DMSO-D₆) δ: 7.79- 7.73 (2H, m), 7.61-7.57 (1H, m), 7.49-7.43 (1H, m), 7.33- 7.23 (2H, m), 7.17-7.15 (1H, m), 7.11-7.06 (1H, m), 4.54- 4.45 (1H, m), 4.23-4.07 (4H, m), 3.73-3.62 (2H, m), 3.00 (1.6H, s), 2.94 (1.4H, s). 349

¹H-NMR (DMSO-D₆) δ: 8.32 (1H, d, J = 7.5 Hz), 7.84-7.82 (1H, m), 7.78 (1H, d, J = 1.3 Hz), 7.77-7.73 (1H, m), 7.65- 7.61 (1H, m), 7.58-7.53 (1H, m), 7.57 (1H, s), 7.35 (1H, br s), 7.26 (1H, br s), 4.56-4.48 (1H, m), 4.45-4.39 (1H, m), 4.32-4.23 (2H, m), 4.01-3.93 (1H, m), 3.84 (2H, s).

TABLE 1-51 compound No. structural formula NMR 350

¹H-NMR (DMSO-D₆) δ: 7.91 (1H, d, J = 7.7 Hz), 7.73-7.69 (2H, m), 7.59-7.54 (2H, m), 7.48-7.44 (1H, m), 7.33 (1H, s), 5.76 (1H, d, J = 6.3 Hz), 4.55-4.53 (2H, m), 4.31-4.23 (1H, m), 4.13-4.00 (1H, m), 3.87-3.75 (1H, m), 2.68 (3H, s). 351

¹H-NMR (DMSO-D₆) δ: 7.91 (1H, d, J = 7.7 Hz), 7.73-7.69 (2H, m), 7.59-7.54 (2H, m), 7.48-7.43 (1H, m), 7.33 (1H, s), 4.83 (1H, t, J = 5.4 Hz), 4.38-4.31 (1H, m), 4.09-4.03 (2H, m), 3.82-3.78 (1H, m), 3.56 (2H, t, J = 5.7 Hz), 2.78- 2.70 (1H, m), 2.68 (3H, s). 352

¹H-NMR (DMSO-D₆) δ: 7.93- 7.90 (1H, m), 7.74-7.69 (2H, m), 7.60-7.54 (2H, m), 7.48- 7.44 (1H, m), 7.35 (1H, br s), 7.33 (1H, s), 7.26 (1H, br s), 4.54-4.45 (1H, m), 4.44-4.38 (1H, m), 4.31-4.21 (2H, m), 3.99-3.92 (1H, m), 3.83 (2H, s), 2.69 (3H, s). 353

¹H-NMR (DMSO-D₆) δ: 7.84- 7.79 (2H, m), 7.64-7.61 (1H, m), 7.56-7.54 (1H, m), 7.52- 7.48 (1H, m), 7.42-7.35 (2H, m), 7.23 (1H, s), 3.79 (2H, s), 3.64 (3H, s). 354

¹H-NMR (DMSO-D₆) δ: 8.03 (1H, s), 7.69-7.65 (1H, m), 7.65 (1H, d, J = 0.7 Hz), 7.60- 7.59 (1H, m), 7.42-7.35 (4H, m), 7.30 (1H, d, J = 1.4 Hz), 3.96 (3H, s), 2.99 (6H, s). 355

¹H-NMR (DMSO-D₆) δ: 8.04 (1H, s), 7.83-7.81 (1H, m), 7.70-7.67 (1H, m), 7.66 (1H, d, J = 0.7 Hz), 7.49 (1H, d, J = 1.6 Hz), 7.43-7.36 (4H, m), 4.38-4.32 (2H, m), 4.10- 4.04 (2H, m), 3.97 (3H, s), 2.32-2.23 (2H, m). 356

¹H-NMR (DMSO-D₆) δ: 8.03 (1H, s), 7.72-7.70 (1H, m), 7.69-7.65 (1H, m), 7.66 (1H, d, J = 0.9 Hz), 7.43-7.34 (5H, m), 3.96 (3H, s), 3.51-3.42 (4H, m), 1.91-1.81 (4H, m).

TABLE 1-52 compound No. structural formula NMR 357

¹H-NMR (DMSO-D₆) δ: 7.78- 7.74 (2H, m), 7.61-7.58 (1H, m), 7.49-7.44 (1H, m), 7.33- 7.29 (1H, m), 7.27 (1H, s), 7.16-7.14 (1H, m), 7.07 (1H, dd, J = 8.3, 2.6 Hz), 4.88 (2H, s), 3.72 (3H, s). 358

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, s), 7.64-7.57 (2H, m), 7.60 (1H, s), 7.41 (1H, br s), 7.30-7.25 (3H, m), 7.24 (1H, s), 7.23-7.20 (1H, m), 6.84 (1H, d, J = 2.6 Hz), 4.50 (2H, s), 3.96 (3H, s). 359

¹H-NMR (CDCl₃) δ: 7.69-7.64 (1H, m), 7.58-7.54 (2H, m), 7.47-7.41 (1H, m), 7.32-7.23 (2H, m), 6.97 (1H, dd, J = 8.5, 2.4 Hz), 4.17 (2H, t, J = 5.3 Hz), 3.71-3.67 (2H, m), 3.59 (2H, t, J = 7.2 Hz), 3.11 (1H, br s), 2.38 (2H, t, J = 8.3 Hz), 2.09-1.98 (2H, m). 360

¹H-NMR (DMSO-D₆) δ: 7.74 (2H, d, J = 8.3 Hz), 7.60-7.57 (1H, m), 7.48-7.44 (1H, m), 7.32-7.28 (1H, m), 7.25 (1H, s), 7.17-7.14 (1H, m), 7.03 (1H, dd, J = 8.3, 2.3 Hz), 4.79 (2H, s), 3.52-3.46 (2H, m), 3.36-3.31 (2H, m), 1.95-1.87 (2H, m), 1.82-1.74 (2H, m). 361

¹H-NMR (DMSO-D₆) δ: 7.76- 7.73 (2H, m), 7.60-7.57 (1H, m), 7.48-7.44 (1H, m), 7.32- 7.28 (1H, m), 7.24 (1H, s), 7.16-7.14 (1H, m), 7.03 (1H, dd, J = 8.3, 2.6 Hz), 4.87 (2H, s), 3.46-3.40 (4H, m), 1.63- 1.52 (4H, m), 1.47-1.42 (2H, m). 362

¹H-NMR (DMSO-D₆) δ: 7.77- 7.73 (2H, m), 7.61-7.58 (1H, m), 7.48-7.44 (1H, m), 7.32- 7.28 (1H, m), 7.25 (1H, s), 7.18-7.16 (1H, m), 7.05 (1H, dd, J = 8.5, 2.4 Hz), 4.91 (2H, s), 3.64-3.55 (4H, m), 3.52- 3.44 (4H, m). 363

¹H-NMR (DMSO-D₆) δ: 9.38 (1H, s), 8.96 (2H, br s), 7.67- 7.62 (2H, m), 7.43 (1H, br s), 7.40-7.37 (1H, m), 7.39 (1H, s), 7.31-7.22 (2H, m), 7.05 (1H, d, J = 2.4 Hz), 6.64 (1H, d, J = 7.1 Hz), 4.56 (2H, s).

TABLE 1-53 compound No. structural formula NMR 364

¹H-NMR (DMSO-D₆) δ: 9.41 (1H, s), 9.01 (2H, br s), 8.31- 8.28 (1H, m), 8.01 (1H, d, J = 1.4 Hz), 7.77-7.73 (1H, m), 7.63 (1H, s), 7.49-7.44 (1H, m), 7.38-7.33 (1H, m), 6.75 (1H, d, J = 7.9 Hz), 3.92 (3H, s). 365

¹H-NMR (DMSO-D₆) δ: 8.13 (1H, t, J = 5.6 Hz), 7.79-7.74 (2H, m), 7.62-7.58 (1H, m), 7.49-7.44 (1H, m), 7.33-7.29 (1H, m), 7.27-7.23 (1H, m), 7.26 (1H, s), 7.09 (1H, dd, J = 8.3, 2.6 Hz), 4.73 (1H, t, J = 5.6 Hz), 4.54 (2H, s), 3.47- 3.42 (2H, m), 3.25-3.20 (2H, m). 366

¹H-NMR (DMSO-D₆) δ: 7.76- 7.71 (2H, m), 7.60-7.57 (1H, m), 7.48-7.43 (1H, m), 7.32- 7.27 (1H, m), 7.24 (1H, s), 7.16-7.14 (1H, m), 7.04-7.00 (1H, m), 5.00 (0.6H, t, J = 5.1 Hz), 4.96 (1.2H, s), 4.88 (0.8H, s), 4.69 (0.4H, t, J = 5.6 Hz), 3.61-3.57 (1.2H, m), 3.51-3.47 (0.8H, m), 3.42- 3.33 (2H, m), 3.06 (1.2H, s), 2.86 (1.8H, s). 367

¹H-NMR (DMSO-D₆) δ: 13.42 (1H, br s), 9.41 (1H, s), 9.01 (2H, br s), 8.30-8.28 (1H, m), 7.97 (1H, d, J = 1.4 Hz), 7.76- 7.72 (1H, m), 7.58 (1H, s), 7.48-7.43 (1H, m), 7.37-7.32 (1H, m), 6.74 (1H, d, J = 7.7 Hz). 368

¹H-NMR (DMSO-D₆) δ: 9.39 (1H, s), 9.00 (2H, br s), 7.78- 7.76 (1H, m), 7.74-7.69 (1H, m), 7.52-7.51 (2H, m), 7.44- 7.39 (1H, m), 7.35-7.30 (1H, m), 6.74 (1H, d, J = 7.7 Hz), 3.02 (6H, s). 369

¹H-NMR (DMSO-D₆) δ: 9.40 (1H, s), 8.99 (2H, br s), 7.99- 7.97 (1H, m), 7.74-7.70 (1H, m), 7.66 (1H, d, J = 1.6 Hz), 7.54 (1H, s), 7.45-7.40 (1H, m), 7.35-7.31 (1H, m), 6.75 (1H, d, J = 7.7 Hz), 4.42- 4.34 (2H, m), 4.13-4.05 (2H, m), 2.33-2.24 (2H, m). 370

¹H-NMR (DMSO-D₆) δ: 9.39 (1H, s), 9.00 (2H, br s), 7.89- 7.86 (1H, m), 7.74-7.70 (1H, m), 7.62 (1H, d, J = 1.6 Hz), 7.51 (1H, s), 7.44-7.39 (1H, m), 7.35-7.30 (1H, m), 6.75 (1H, d, J = 7.7 Hz), 3.56-3.44 (4H, m), 1.93-1.81 (4H, m).

TABLE 1-54 compound No. structural formula NMR 371

¹H-NMR (DMSO-D₆) δ: 9.41 (1H, s), 9.02 (2H, br s), 8.67 (1H, t, J = 5.7 Hz), 8.29-8.25 (1H, m), 7.95 (1H, d, J = 1.6 Hz), 7.75- 7.71 (1H, m), 7.51 (1H, s), 7.45-7.40 (1H, m), 7.36- 7.31 (1H, m), 6.79 (1H, d, J = 7.7 Hz), 4.41 (1H, t, J = 5.1 Hz), 3.45-3.39 (2H, m), 3.37-3.25 (2H, m), 1.61-1.52 (2H, m), 1.51- 1.42 (2H, m). 372

¹H-NMR (DMSO-D₆) δ: 9.39 (1H, s), 8.99 (2H, br s), 7.79-7.76 (1H, m), 7.73- 7.69 (1H, m), 7.54-7.48 (2H, m), 7.43-7.38 (1H, m), 7.34-7.29 (1H, m), 6.75 (1H, d, J = 7.7 Hz), 4.88- 4.79 (1H, m), 3.67-3.60 (1H, m), 3.57-3.50 (2H, m), 3.41-3.36 (1H, m), 3.06- 2.99 (3H, m). 373

¹H-NMR (DMSO-D₆) δ: 8.04 (1H, s), 7.82-7.79 (1H, m), 7.70-7.65 (1H, m), 7.66 (1H, s), 7.48 (1H, d, J = 1.5 Hz), 7.43-7.36 (4H, m), 5.76 (1H, d, J = 5.7 Hz), 4.54-4.47 (2H, m), 4.31- 4.24 (1H, m), 4.09-4.03 (1H, m), 3.97 (3H, s), 3.84-3.78 (1H, m). 374

H-NMR (DMSO-D₆) δ: 8.03 (1H, s), 7.84-7.81 (1H, m), 7.71-7.66 (1H, m), 7.65 (1H, d, J = 0.7 Hz), 7.52- 7.48 (1H, m), 7.42-7.36 (4H, m), 4.83 (1H, t, J = 5.4 Hz), 4.39-4.32 (1H, m), 4.12-4.02 (2H, m), 3.97 (3H, s), 3.84-3.77 (1H, m), 3.55 (2H, t, J = 5.5 Hz), 2.79-2.69 (1H, m). 375

¹H-NMR (DMSO-D₆) δ: 8.04 (1H, s), 7.84-7.81 (1H, m), 7.70-7.66 (2H, m), 7.51- 7.48 (1H, m), 7.44-7.35 (4H, m), 4.66 (1H, t, J = 5.4 Hz), 4.55-4.46 (1H, m), 4.41-4.35 (1H, m), 4.32- 4.24 (1H, m), 4.19-4.13 (1H, m), 3.97 (3H, s), 3.92-3.86 (1H, m), 3.53- 3.48 (2H, m), 3.44-3.39 (2H, m). 376

¹H-NMR (DMSO-D₆) δ: 8.04 (1H, s), 7.72-7.65 (3H, m), 7.44-7.34 (5H, m), 5.04- 4.95 (1H, m), 4.37-4.23 (1H, m), 3.96 (3H, s), 3.68-3.24 (4H, m), 2.03- 1.88 (1H, m), 1.87-1.77 (1H, m).

TABLE 1-55 compound No. structural formula NMR 377

¹H-NMR (DMSO-D₆) δ: 8.25 (1H, s), 7.93 (1H, d, J = 0.7 Hz), 7.85-7.81 (2H, m), 7.79-7.77 (1H, m), 7.71 (1H, dd, J = 7.9, 1.5 Hz), 7.65-7.61 (1H, m), 7.52- 7.47 (1H, m), 7.39-7.34 (1H, m), 7.25 (1H, s), 3.88 (3H, s). 378

¹H-NMR (DMSO-D₆) δ: 8.36 (1H, d, J = 2.6 Hz), 7.79 (1H, d, J = 7.5 Hz), 7.71- 7.66 (1H, m), 7.59-7.53 (2H, m), 7.49 (1H, s), 7.48-7.43 (1H, m), 3.91 (3H, s). 379

¹H-NMR (DMSO-D₆) δ: 7.79- 7.73 (2H, m), 7.61-7.56 (1H, m), 7.49-7.43 (1H, m), 7.33-7.27 (1H, m), 7.24 (0.4H, s), 7.23 (0.6H, s), 7.18-7.14 (1H, m), 7.11- 7.06 (1H, m), 4.85 (0.6H, t, J = 5.5 Hz), 4.68 (0.4H, t, J = 5.3 Hz), 4.20 (0.8H, t, J = 5.5 Hz), 4.12 (1.2H, t, J = 6.0 Hz), 3.79-3.73 (0.8H, m), 3.69-3.63 (1.2H, m), 3.61-3.54 (1.2H, m), 3.51-3.38 (2.8H, m), 2.10 (1.2H, s), 2.05 (1.8H, s). 380

¹H-NMR (DMSO-D₆) δ: 7.77- 7.72 (2H, m), 7.60-7.56 (1H, m), 7.49-7.43 (1H, m), 7.32-7.21 (2H, m), 7.17- 7.13 (1H, m), 7.11-7.04 (1H, m), 4.82-4.65 (1H, m), 3.71-3.62 (0.4H, m), 3.52- 3.39 (1.6H, m), 3.03 (1.8H, s), 2.85 (0.6H, s), 2.84 (0.6H, s), 2.10 (1.2H, s), 1.96 (0.9H, s), 1.95 (0.9H, s), 1.29-1.21 (3H, m). 381

¹H-NMR (DMSO-D₆) δ: 7.79- 7.73 (2H, m), 7.61-7.56 (1H, m), 7.49-7.43 (1H, m), 7.33-7.27 (1H, m), 7.25- 7.22 (1H, m), 7.18-7.14 (1H, m), 7.11-7.05 (1H, m), 4.92-4.79 (0.5H, m), 4.37- 4.25 (0.5H, m), 4.15-3.96 (2H, m), 2.88 (1.5H, s), 2.70 (1.5H, s), 2.05 (1.5H, s), 2.00 (1.5H, s), 1.25- 1.13 (3H, m). 382

¹H-NMR (DMSO-D₆) δ: 7.76- 7.72 (2H, m), 7.60-7.57 (1H, m), 7.48-7.43 (1H, m), 7.32-7.28 (1H, m), 7.24 (1H, s), 7.16-7.12 (1H, m), 7.05-7.01 (1H, m), 5.14- 5.10 (0.3H, m), 4.93 (0.6H, s), 4.80-4.77 (1.4H, m), 4.73 (0.7H, t, J = 5.6 Hz), 4.12-4.04 (0.3H, m), 4.01- 3.94 (0.7H, m), 3.55-3.26 (4H, m), 2.01-1.76 (4H, m).

TABLE 1-56 compound No. structural formula NMR 383

¹H-NMR (DMSO-D₆) δ: 7.76- 7.72 (2H, m), 7.61-7.57 (1H, m), 7.48-7.43 (1H, m), 7.32-7.28 (1H, m), 7.24 (1H, s), 7.16-7.13 (1H, m), 7.05-7.01 (1H, m), 5.14- 5.10 (0.3H, m), 4.95-4.91 (0.6H, m), 4.81-4.77 (1.4H, m), 4.75-4.71 (0.7H, m), 4.12-4.04 (0.3H, m), 4.00- 3.94 (0.7H, m), 3.55-3.26 (4H, m), 2.00-1.76 (4H, m). 384

¹H-NMR (DMSO-D₆) δ: 12.03 (1H, br s), 8.14 (1H, d, J = 7.7 Hz), 7.68-7.64 (1H, m), 7.56-7.51 (1H, m), 7.42-7.38 (2H, m), 7.17- 7.14 (2H, m), 4.08 (2H, t, J = 6.3 Hz), 2.30 (2H, t, J = 7.2 Hz), 1.80-1.72 (2H, m), 1.71-1.64 (2H, m). 385

¹H-NMR (DMSO-D₆) δ: 8.15 (1H, d, J = 7.5 Hz), 7.69- 7.64 (2H, m), 7.57-7.52 (1H, m), 7.48-7.39 (3H, m), 7.27-7.25 (1H, m), 7.15 (1H, d, J = 2.4 Hz), 4.55 (2H, s). 386

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, s), 7.67-7.59 (2H, m), 7.61 (1H, s), 7.41-7.26 (5H, m), 7.21 (1H, s), 4.03 (2H, d, J = 7.3 Hz), 2.27- 2.16 (1H, m), 0.93 (3H, d, J = 2.0 Hz), 0.92 (3H, d, J = 2.0 Hz). 387

¹H-NMR (CDCl₃) δ: 8.20 (1H, d, J = 7.9 Hz), 7.70-7.65 (1H, m), 7.50-7.46 (1H, m), 7.36-7.31 (1H, m), 7.20- 7.17 (1H, m), 6.95 (1H, d, J = 2.2 Hz), 4.02 (2H, t, J = 6.4 Hz), 3.68 (2H, t, J = 6.3 Hz), 2.88 (1H, br s), 1.88-1.80 (2H, m), 1.69- 1.61 (4H, m). 388

¹H-NMR (CDCl₃) δ: 8.22-8.17 (1H, m), 7.71-7.66 (1H, m), 7.51-7.45 (1H, m), 7.37- 7.30 (1H, m), 7.20-7.16 (1H, m), 6.95-6.92 (1H, m), 4.16-4.09 (2H, m), 3.90 (0.7H, br s), 3.77 (0.3H, br s), 3.73-3.61 (2H, m), 3.13 (2.2H, s), 2.96 (0.8H, s), 2.14 (0.8H, s), 2.03 (2.2H, s). 389

¹H-NMR (DMSO-D₆) δ: 7.75 (2H, d, J = 8.3 Hz), 7.61- 7.57 (1H, m), 7.48-7.43 (1H, m), 7.32-7.28 (1H, m), 7.25 (1H, s), 7.18-7.15 (1H, m), 7.04 (1H, dd, J = 8.5, 2.4 Hz), 5.07 (0.5H, d, J = 3.7 Hz), 4.96 (0.5H, d, J = 3.2 Hz), 4.81 (1.0H, s), 4.76 (1.0H, s), 4.36 (0.5H, d, J = 20.4 Hz), 4.27 (0.5H, d, J = 18.3 Hz), 3.65-3.53 (1.5H, m), 3.49-3.27 (2.5H, m), 2.01- 1.92 (0.5H, m), 1.91-1.81 (1.0H, m), 1.79-1.71 (0.5H, m).

TABLE 1-57 compound No. structural formula NMR 390

¹H-NMR (DMSO-D₆) δ: 7.74 (2H, d, J = 8.1 Hz), 7.60- 7.56 (1H, m), 7.47-7.43 (1H, m), 7.32-7.27 (1H, m), 7.25 (1H, s), 7.17-7.14 (1H, m), 7.03 (1H, dd, J = 8.5, 2.4 Hz), 5.06 (0.5H, d, J = 3.7 Hz), 4.96 (0.5H, d, J = 3.2 Hz), 4.80 (1.0H, s), 4.75 (1.0H, s), 4.38- 4.33 (0.5H, m), 4.28-4.24 (0.5H, m), 3.64-3.52 (1.5H, m), 3.48-3.23 (2.5H, m), 1.99-1.91 (0.5H, m), 1.90- 1.80 (1.0H, m), 1.78-1.69 (0.5H, m). 391

¹H-NMR (DMSO-D₆) δ: 7.78- 7.74 (2H, m), 7.61-7.58 (1H, m), 7.49-7.44 (1H, m), 7.33-7.28 (1H, m), 7.26 (1H, s), 7.16-7.14 (1H, m), 7.04 (1H, dd, J = 8.3, 2.6 Hz), 4.64 (2H, s), 4.26 (2H, t, J = 8.5 Hz), 3.92 (2H, t, J = 7.8 Hz), 2.30- 2.20 (2H, m). 392

¹H-NMR (DMSO-D₆) δ: 8.02 (1H, s), 7.73-7.63 (2H, m), 7.65 (1H, s), 7.43-7.32 (5H, m), 4.82-4.76 (1H, m), 4.21-4.12 (1H, m), 3.96 (3H, s), 3.61-3.55 (2H, m), 3.51-3.44 (1H, m), 3.41- 3.34 (1H, m), 2.02-1.83 (3H, m), 1.77-1.64 (1H, m). 393

¹H-NMR (DMSO-D₆) δ: 8.03 (1H, s), 7.73-7.63 (2H, m), 7.65 (1H, s), 7.43-7.32 (5H, m), 4.82-4.75 (1H, m), 4.21-4.12 (1H, m), 3.96 (3H, s), 3.61-3.54 (2H, m), 3.51-3.44 (1H, m), 3.43- 3.34 (1H, m), 2.01-1.82 (3H, m), 1.78-1.66 (1H, m). 394

¹H-NMR (DMSO-D₆) δ: 8.03 (1H, s), 7.72-7.64 (3H, m), 7.42-7.34 (5H, m), 4.73- 4.62 (1H, m), 3.96 (3H, s), 3.63-3.24 (6H, m), 2.39- 2.26 (1H, m), 2.00-1.86 (1H, m), 1.71-1.60 (1H, m). 395

¹H-NMR (CDCl₃) δ: 7.68-7.64 (1H, m), 7.57-7.51 (2H, m), 7.46-7.40 (1H, m), 7.30- 7.23 (2H, m), 6.97 (1H, dd, J = 8.3, 2.3 Hz), 4.04 (2H, t, J = 6.2 Hz), 3.52-3.38 (5H, m), 2.36-2.29 (2H, m), 2.06-1.95 (4H, m).

TABLE 1-58 compound No. structural formula NMR 396

¹H-NMR (DMSO-D₆) δ: 7.77- 7.73 (2H, m), 7.61-7.58 (1H, m), 7.49-7.44 (1H, m), 7.33-7.28 (1H, m), 7.25 (1H, s), 7.17-7.14 (1H, m), 7.03 (1H, dd, J = 8.3, 2.6 Hz), 4.91 (1H, d, J = 13.9 Hz), 4.86 (1H, d, J = 15.5 Hz), 4.78 (1H, d, J = 3.7 Hz), 3.92-3.84 (1H, m), 3.76-3.65 (2H, m), 3.25- 3.15 (1H, m), 3.12-3.01 (1H, m), 1.83-1.66 (2H, m), 1.47-1.35 (1H, m), 1.32- 1.21 (1H, m). 397

¹H-NMR (DMSO-D₆) δ: 7.77- 7.73 (2H, m), 7.61-7.57 (1H, m), 7.48-7.44 (1H, m), 7.32-7.28 (1H, m), 7.25 (1H, s), 7.16-7.13 (1H, m), 7.04 (1H, dd, J = 8.3, 2.3 Hz), 4.95-4.81 (2H, m), 4.52 (1H, t, J = 5.1 Hz), 4.38-4.29 (1H, m), 3.92- 3.83 (1H, m), 3.26 (2H, t, J = 5.6 Hz), 3.07-2.97 (1H, m), 2.63-2.54 (1H, m), 1.75-1.58 (3H, m), 1.21- 1.07 (1H, m), 1.03-0.90 (1H, m). 398

¹H-NMR (CDCl₃) δ: 8.15 (1H, d, J = 2.2 Hz), 7.81 (1H, d, J = 7.5 Hz), 7.72 (1H, d, J = 7.5 Hz), 7.53-7.47 (2H, m), 7.43-7.38 (1H, m), 4.18-4.03 (2H, m), 3.76- 3.67 (3H, m), 3.15 (2.3H, s), 2.98 (0.7H, s), 2.16 (0.7H, s), 2.06 (2.3H, s). 399

¹H-NMR (CDCl₃) δ: 8.16-8.12 (1H, m), 7.86-7.81 (1H, m), 7.74-7.69 (1H, m), 7.56- 7.48 (1H, m), 7.48-7.38 (2H, m), 4.27-4.12 (4H, m), 3.89-3.49 (4H, m), 3.09 (0.7H, s), 3.04 (2.3H, s). 400

¹H-NMR (DMSO-D₆) δ: 7.76- 7.71 (2H, m), 7.61-7.57 (1H, m), 7.48-7.44 (1H, m), 7.30 (1H, d, J = 18.6 Hz), 7.24 (1H, s), 7.16-7.13 (1H, m), 7.01 (1H, dd, J = 8.5, 2.4 Hz), 5.02 (1H, t, J = 5.1 Hz), 4.97 (2H, s), 4.71 (1H, t, J = 5.4 Hz), 3.63-3.57 (2H, m), 3.53- 3.32 (6H, m). 401

¹H-NMR (CDCl₃) δ: 7.69-7.65 (1H, m), 7.58-7.52 (2H, m), 7.45-7.40 (1H, m), 7.30- 7.25 (2H, m), 6.97 (1H, dd, J = 8.4, 2.4 Hz), 4.05 (2H, t, J = 6.2 Hz), 3.74 (1H, s), 3.62-3.54 (1H, m), 3.47-3.39 (1H, m), 3.34- 3.27 (2H, m), 2.33-2.28 (2H, m), 2.06-1.99 (2H, m), 1.81-1.71 (4H, m). 402

¹H-NMR (DMSO-D₆) δ: 12.39 (1H, br s), 7.83 (1H, d, J = 7.7 Hz), 7.79 (1H, d, J = 7.9 Hz), 7.65-7.61 (1H, m), 7.56-7.53 (1H, m), 7.52- 7.47 (1H, m), 7.41-7.35 (2H, m), 7.24 (1H, s), 3.67 (2H, s).

TABLE 1-59 compound No. structural formula NMR 403

¹H-NMR (DMSO-D₆) δ: 7.81 (1H, d, J = 7.5 Hz), 7.77 (1H, d, J = 7.7 Hz), 7.64- 7.60 (1H, m), 7.58-7.52 (2H, m), 7.51-7.46 (1H, m), 7.41-7.34 (2H, m), 7.22 (1H, s), 6.92 (1H, br s), 3.47 (1H, d, J = 14.1 Hz), 3.43 (1H, d, J = 14.3 Hz). 404

¹H-NMR (CDCl₃) δ: 8.39-8.36 (1H, m), 7.69-7.65 (1H, m), 7.52-7.47 (1H, m), 7.37- 7.32 (1H, m), 7.26 (2H, s), 7.23-7.21 (1H, m), 7.14 (1H, d, J = 2.4 Hz), 4.09 (2H, t, J = 6.1 Hz), 2.61 (2H, t, J = 7.2 Hz), 2.20- 2.12 (2H, m). 405

¹H-NMR (DMSO-D₆) δ: 7.80 (1H, d, J = 7.5 Hz), 7.74 (1H, d, J = 7.7 Hz), 7.64- 7.59 (1H, m), 7.51-7.45 (2H, m), 7.38-7.32 (2H, m), 7.18 (1H, s), 4.68 (1H, t, J = 5.1 Hz), 3.64 (2H, dt, J = 6.8, 5.1 Hz), 2.80 (2H, t, J = 6.8 Hz). 406

¹H-NMR (CDCl₃) δ: 9.20 (1H, s), 8.98-7.98 (2H, m), 7.72-7.69 (1H, m), 7.42- 7.39 (1H, m), 7.25-7.21 (1H, m), 7.11-7.07 (1H, m), 6.69 (1H, d, J = 2.3 Hz), 6.46 (1H, d, J = 7.9 Hz), 4.48 (1H, s), 4.10-4.04 (2H, m), 3.70 (2H, t, J = 6.1 Hz), 1.90-1.83 (2H, m), 1.71-1.54 (4H, m), 1.41 (1H, br s). 407

¹H-NMR (CDCl₃) δ: 7.68-7.63 (1H, m), 7.54 (1H, d, J = 0.7 Hz), 7.49 (1H, s), 7.25-7.21 (4H, m), 6.78 (1H, d, J = 2.3 Hz), 4.04 (2H, t, J = 6.4 Hz), 4.00 (3H, s), 3.69 (2H, t, J = 6.3 Hz), 3.24 (1H, br s), 1.89-1.81 (2H, m), 1.70- 1.52 (4H, m), 1.34 (1H, br s). 408

¹H-NMR (DMSO-D₆) δ: 8.15 (1H, d, J = 7.7 Hz), 7.69- 7.65 (1H, m), 7.57-7.52 (1H, m), 7.44 (1H, s), 7.43-7.39 (1H, m), 7.21 (1H, d, J = 2.2 Hz), 7.20- 7.18 (1H, m), 4.24 (2H, t, J = 5.4 Hz), 3.50 (2H, t, J = 5.4 Hz), 2.95 (3H, s), 2.89 (3H, s). 409

¹H-NMR (DMSO-D₆) δ: 8.15- (1H, d, J = 7.7 Hz), 7.68- 7.64 (1H, m), 7.56-7.52 (1H, m), 7.46-7.38 (2H, m), 7.20-7.16 (2H, m), 4.53 (0.4H, t, J = 5.4 Hz), 4.48 (0.6H, t, J = 5.5 Hz), 4.26-4.17 (3H, m), 4.09 (1H, d, J = 5.5 Hz), 3.70 (1.1H, t, J = 5.7 Hz), 3.64 (0.9H, t, J = 5.1 Hz), 2.99 (1.6H, s), 2.93 (1.4H, s). 410

¹H-NMR (DMSO-D₆) δ: 8.14 (1H, d, J = 7.7 Hz), 7.68- 7.63 (1H, m), 7.56-7.51 (1H, m), 7.46-7.38 (2H, m), 7.33 (1H, br s), 7.16 (2H, s), 6.79 (1H, br s), 4.07 (2H, t, J = 6.4 Hz), 2.24 (2H, t, J = 7.4 Hz), 1.98- 1.90 (2H, m).

TABLE 1-60 compound No. structural formula NMR 411

¹H-NMR (CDCl₃) δ: 7.73-7.67 (2H, m), 7.59 (1H, s), 7.57 (1H, s), 7.37-7.23 (5H, m), 4.36-4.32 (2H, m), 4.13- 4.06 (2H, m), 3.07 (1H, br s), 2.96 (1H, br s). 412

¹H-NMR (CDCl₃) δ: 7.68-7.63 (1H, m), 7.59 (1H, s), 7.50 (1H, s), 7.28-7.21 (4H, m), 6.77 (1H, d, J = 2.6 Hz), 4.16 (2H, t, J = 5.2 Hz), 4.02 (3H, s), 3.71-3.66 (2H, m), 3.62-3.56 (2H, m), 3.15 (1H, br s), 2.40-2.35 (2H, m), 2.08-1.99 (2H, m). 413

¹H-NMR (DMSO-D₆) δ: 7.78- 7.72 (2H, m), 7.65-7.56 (2H, m), 7.48-7.43 (1H, m), 7.32-7.27 (2H, m), 7.24 (1H, d, J = 4.6 Hz), 7.20- 7.16 (1H, m), 7.05-7.01 (1H, m), 4.71-4.64 (1H, m), 1.49-1.44 (3H, m). 414

¹H-NMR (CDCl₃) δ: 7.93-7.91 (1H, m), 7.83-7.79 (1H, m), 7.61 (1H, d, J = 0.7 Hz), 7.53 (1H, d, J = 1.6 Hz), 7.47-7.45 (1H, m), 7.40- 7.33 (2H, m), 7.29-7.25 (1H, m), 6.20 (1H, br s), 4.10-3.97 (2H, m), 4.04 (3H, s), 3.25-3.18 (2H, m). 415

¹H-NMR (CDCl₃) δ: 7.71-7.69 (1H, m), 7.65-7.57 (3H, m), 7.55-7.45 (1H, m), 7.39- 7.33 (2H, m), 5.84 (1H, br s), 4.50-4.39 (2H, m), 3.36 (1H, br s), 2.01 (3H, s). 416

¹H-NMR (CDCl₃) δ: 7.69-7.65 (1H, m), 7.58-7.53 (2H, m), 7.46-7.41 (1H, m), 7.31- 7.24 (2H, m), 6.97 (1H, dd, J = 8.4, 2.4 Hz), 4.20 (2H, t, J = 5.4 Hz), 3.77-3.65 (2H, m), 3.55-3.44 (3H, m), 2.33 (2H, t, J = 6.3 Hz), 1.84-1.71 (4H, m). 417

¹H-NMR (CDCl₃) δ: 7.76-7.72 (1H, m), 7.65-7.60 (2H, m), 7.53 (1H, d, J = 7.7 Hz), 7.48-7.43 (1H, m), 7.37- 7.33 (1H, m), 7.23-7.20 (1H, m), 3.57 (1H, d, J = 13.2 Hz), 3.45 (1H, d, J = 13.2 Hz), 2.09 (3H, s).

TABLE 1-61 compound No. structural formula NMR 418

¹H-NMR (DMSO-D₆) δ: 7.87- 7.79 (2H, m), 7.65-7.61 (1H, m), 7.53-7.46 (2H, m), 7.40-7.33 (2H, m), 7.30 (0.4H, s), 7.24 (0.6H, s), 4.65 (0.8H, s), 4.59 (0.6H, d, J = 15.2 Hz), 4.53 (0.6H, d, J = 15.0 Hz), 2.94 (1.8H, s), 2.82 (1.2H, s), 2.09 (1.8H, s), 2.06 (1.2H, s). 419

¹H-NMR (CDCl₃) δ: 7.69-7.65 (1H, m), 7.58-7.54 (2H, m), 7.47-7.42 (1H, m), 7.32- 7.27 (1H, m), 7.25-7.22 (1H, m), 6.99-6.95 (1H, m), 5.99 (1H, br s), 4.11-4.04 (2H, m), 3.90-3.84 (1H, m), 3.69 (1H, s), 2.48-2.29 (3H, m), 1.98-1.87 (1H, m). 420

¹H-NMR (CDCl₃) δ: 7.69-7.65 (1H, m), 7.59-7.55 (2H, m), 7.47-7.43 (1H, m), 7.32- 7.28 (1H, m), 7.25-7.23 (1H, m), 7.00-6.96 (1H, m), 4.17-4.13 (1H, m), 4.07- 4.02 (1H, m), 3.94-3.88 (1H, m), 3.17-3.07 (1H, m), 2.92 (2H, s), 2.90 (1H, s), 2.60-2.48 (1H, m), 2.43- 2.33 (1H, m), 2.31-2.20 (1H, m), 2.03-1.94 (1H, m). 421

¹H-NMR (CDCl₃) δ: 7.69-7.65 (1H, m), 7.59-7.55 (2H, m), 7.47-7.43 (1H, m), 7.32- 7.28 (1H, m), 7.24-7.22 (1H, m), 6.99-6.95 (1H, m), 4.18-4.13 (1H, m), 4.07- 4.03 (1H, m), 4.01-3.95 (1H, m), 3.73 (1H, br s), 3.61-3.52 (2H, m), 3.51- 3.42 (2H, m), 3.31-3.25 (1H, m), 2.66-2.56 (1H, m), 2.48-2.39 (1H, m), 2.33- 2.23 (1H, m), 2.07-1.98 (1H, m), 1.75-1.52 (2H, m). 422

¹H-NMR (DMSO-D₆) δ: 9.38 (0.5H, s), 9.37 (0.5H, s), 8.96 (2H, br s), 7.66-7.62 (1H, m), 7.39 (1H, d, J = 6.5 Hz), 7.32-7.22 (3H, m), 7.07 (1H, dd, J = 4.6, 2.3 Hz), 6.65-6.61 (1H, m), 4.26 (1.0H, t, J = 5.2 Hz), 4.18 (1.0H, t, J = 5.8 Hz), 3.73 (1.0H, t, J = 5.2 Hz), 3.66 (1.0H, t, J = 5.9 Hz), 3.08 (1.5H, s), 2.88 (1.5H, s), 2.09 (1.5H, s), 2.00 (1.5H, s). 423

¹H-NMR (CDCl₃) δ: 7.69-7.64 (1H, m), 7.55-7.53 (1H, m), 7.50-7.48 (1H, m), 7.25- 7.20 (4H, m), 6.75 (1H, d, J = 2.6 Hz), 4.18-4.13 (2H, m), 4.00 (2.1H, s), 3.99 (0.9H, s), 3.79-3.62 (3H, m), 3.16 (2.1H, s), 2.98 (0.9H, s), 2.16 (0.9H, s), 2.07 (2.1H, s).

TABLE 1-62 compound No. structural formula NMR 424

¹H-NMR (DMSO-D₆) δ: 9.38 (0.4H, s), 9.37 (0.5H, s), 8.96 (2H, br s), 7.66-7.62 (1H, m), 7.39 (1H, d, J = 7.2 Hz), 7.32-7.22 (3H, m), 7.07 (1H, d, J = 2.3 Hz), 6.63 (1H, dd, J = 7.1, 3.4 Hz), 4.53 (0.4H, t, J = 5.6 Hz), 4.48 (0.5H, t, J = 5.4 Hz), 4.28-4.19 (3H, m), 4.08 (1H, d, J = 5.8 Hz), 3.72 (1.1H, t, J = 5.8 Hz), 3.66 (0.9H, t, J = 5.2 Hz), 2.99 (1.7H, s), 2.94 (1.4H, s). 425

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, s), 7.64-7.58 (1H, m), 7.62 (1H, s), 7.31-7.22 (4H, m), 7.16-7.13 (1H, m), 6.84 (1H, d, J = 2.3 Hz), 4.52 (0.4H, t, J = 5.6 Hz), 4.48 (0.6H, t, J = 5.4 Hz), 4.23-4.14 (3.0H, m), 4.09 (1.0H, d, J = 5.3 Hz), 3.95 (3H, s), 3.70 (1.1H, t, J = 5.7 Hz), 3.64 (0.9H, t, J = 5.2 Hz), 2.99 (1.6H, s), 2.93 (1.4H, s). 426

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, s), 7.66-7.53 (3H, m), 7.31-7.21 (2H, m), 7.22 (1H, s), 7.14-7.12 (1H, m), 6.81 (1H, d, J = 2.4 Hz), 4.46 (1H, t, J = 5.2 Hz), 4.05 (2H, t, J = 6.5 Hz), 3.95 (3H, s), 3.49-3.43 (2H, m), 1.81-1.74 (2H, m), 1.62-1.54 (2H, m). 427

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, s), 7.62-7.57 (1H, m), 7.61 (1H, s), 7.29-7.23 (3H, m), 7.22 (1H, s), 7.15-7.12 (1H, m), 6.82 (1H, d, J = 2.4 Hz), 4.07 (2H, t, J = 6.5 Hz), 3.95 (3H, s), 2.97 (3H, s), 2.83 (3H, s), 2.47 (2H, t, J = 7.3 Hz), 1.99-1.92 (2H, m). 428

¹H-NMR (DMSO-D₆) δ: 9.37 (1H, s), 8.96 (2H, br s), 7.65-7.61 (1H, m), 7.38- 7.35 (1H, m), 7.30-7.21 (3H, m), 7.03 (1H, d, J = 2.4 Hz), 6.61 (1H, d, J = 6.8 Hz), 4.46 (1H, t, J = 5.2 Hz), 4.10 (2H, t, J = 6.5 Hz), 3.47 (2H, dt, J = 6.5, 5.2 Hz), 1.82-1.75 (2H, m), 1.63-1.54 (2H, m). 429

¹H-NMR (DMSO-D₆) δ: 9.37 (1H, s), 8.96 (2H, br s), 7.65-7.62 (1H, m), 7.38 (1H, s), 7.31-7.22 (3H, m), 7.04 (1H, d, J = 2.3 Hz), 6.61 (1H, dd, J = 6.7, 0.9 Hz), 4.11 (2H, t, J = 6.5 Hz), 2.97 (3H, s), 2.82 (3H, s), 2.47 (2H, t, J = 7.0 Hz), 2.01-1.94 (2H, m).

TABLE 1-63 compound No. structural formula NMR 430

¹H-NMR (DMSO-D₆) δ: 8.36 (1H, d, J = 2.8 Hz), 7.81- 7.78 (1H, m), 7.70-7.67 (1H, m), 7.60-7.54 (2H, m), 7.50 (1H, s), 7.48-7.44 (1H, m), 4.25 (2H, t, J = 5.4 Hz), 3.59 (2H, t, J = 5.4 Hz), 3.48 (2H, t, J = 7.1 Hz), 2.22 (2H, t, J = 8.1 Hz), 1.97-1.88 (2H, m). 431

¹H-NMR (CDCl₃) δ: 7.68-7.65 (1H, m), 7.59-7.54 (2H, m), 7.47-7.42 (1H, m), 7.32- 7.27 (1H, m), 7.25-7.23 (1H, m), 7.00-6.96 (1H, m), 4.57-4.52 (2H, m), 4.24- 4.05 (3H, m), 3.84-3.77 (1H, m), 3.70-3.65 (2H, m), 3.42-3.32 (1H, m), 3.31 (1.5H, s), 3.29 (1.5H, s), 3.04 (0.5H, s), 3.00 (0.5H, s), 2.64-2.53 (1H, m), 2.46-2.36 (1H, m), 2.32- 2.21 (1H, m), 2.08-1.98 (1H, m). 432

¹H-NMR (CDCl₃) δ: 7.69-7.65 (1H, m), 7.59-7.55 (2H, m), 7.47-7.43 (1H, m), 7.32- 7.28 (1H, m), 7.25-7.22 (1H, m), 6.98 (1H, dd, J = 8.2, 2.4 Hz), 4.21-4.13 (1H, m), 4.10-4.03 (2H, m), 3.84-3.67 (2H, m), 3.66- 3.57 (1H, m), 3.49-3.42 (1H, m), 3.28 (1H, d, J = 23.9 Hz), 3.23-3.15 (1H, m), 2.65-2.54 (1H, m), 2.47-2.38 (1H, m), 2.37- 2.26 (1H, m), 2.08-1.98 (1H, m). 433

¹H-NMR (DMSO-D₆) δ: 13.07 (1H, br s), 7.97 (1H, s), 7.62-7.58 (1H, m), 7.60 (1H, s), 7.30-7.23 (4H, m), 7.14-7.11 (1H, m), 6.80 (1H, d, J = 2.4 Hz), 4.77 (2H, s), 3.96 (3H, s). 434

¹H-NMR (DMSO-D₆) δ: 8.37 (1H, d, J = 2.8 Hz), 7.80 (1H, d, J = 7.4 Hz), 7.72- 7.67 (2H, m), 7.61-7.59 (1H, m), 7.59-7.54 (1H, m), 7.52 (1H, s), 7.49-7.44 (2H, m), 4.62 (2H, s). 435

¹H-NMR (CDCl₃) δ: 7.69-7.65 (1H, m), 7.59 (0.2H, s), 7.56 (0.8H, s), 7.51 (0.2H, s), 7.50 (0.8H, s), 7.28- 7.22 (4H, m), 6.77 (0.8H, d, J = 2.6 Hz), 6.76 (0.2H, d, J = 2.6 Hz), 5.95 (1H, br s), 4.12-4.08 (2H, m), 4.02 (0.6H, s), 4.02 (2.4H, s), 3.70-3.65 (2H, m), 2.02 (0.6H, s), 2.02 (2.4H, s).

TABLE 1-64 compound No. structural formula NMR 436

¹H-NMR (CDCl₃) δ: 7.73-7.68 (2H, m), 7.52 (1H, s), 7.50 (1H, s), 7.36-7.22 (5H, m), 4.37 (2H, t, J = 6.4 Hz), 3.71 (2H, t, J = 5.7 Hz), 3.34 (1H, br s), 2.59 (1H, br s), 2.16-2.10 (2H, m). 437

¹H-NMR (DMSO-D₆) δ: 8.32 (1H, d, J = 7.9 Hz), 7.68- 7.64 (1H, m), 7.58-7.53 (1H, m), 7.45-7.40 (1H, m), 7.44 (1H, s), 7.28 (1H, d, J = 2.4 Hz), 7.22-7.20 (1H, m), 4.71 (2H, s), 4.28-4.22 (2H, m), 3.95-3.89 (2H, m), 2.30-2.22 (2H, m). 438

¹H-NMR (DMSO-D₆) δ: 8.33 (1H, d, J = 7.7 Hz), 8.19- 8.14 (1H, m), 7.69-7.65 (1H, m), 7.59-7.54 (1H, m), 7.45-7.40 (1H, m), 7.44 (1H, s), 7.33-7.30 (2H, m), 4.58 (2H, s), 2.67 (3H, d, J = 4.6 Hz). 439

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, s), 7.62-7.58 (1H, m), 7.60 (1H, d, J = 0.4 Hz), 7.31-7.24 (4H, m), 7.15- 7.12 (1H, m), 6.81 (1H, d, J = 2.4 Hz), 4.83-4.78 (1H, m), 4.65 (2H, s), 4.29-4.20 (1H, m), 4.01-3.87 (2H, m), 3.96 (3H, s), 3.67-3.61 (1H, m), 3.55-3.50 (2H, m), 2.74-2.65 (1H, m). 440

¹H-NMR (DMSO-D₆) δ: 7.95 (1H, s), 7.61-7.48 (1H, m), 7.59 (1H, d, J = 0.7 Hz), 7.31-7.22 (3H, m), 7.23 (1H, s), 7.14-7.12 (1H, m), 6.81 (1H, d, J = 2.4 Hz), 4.96-4.81 (2H, m), 4.53- 4.49 (1H, m), 4.37-4.30 (1H, m), 3.96 (3H, s), 3.91-3.83 (1H, m), 3.27- 3.22 (2H, m), 3.06-2.96 (1H, m), 2.63-2.53 (1H, m), 1.76-1.57 (3H, m), 1.20- 1.06 (1H, m), 1.01-0.88 (1H, m). 441

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, s), 7.62-7.58 (1H, m), 7.60 (1H, d, J = 0.7 Hz), 7.32-7.24 (3H, m), 7.25 (1H, s), 7.15-7.13 (1H, m), 6.81 (1H, d, J = 2.4 Hz), 4.65 (2H, s), 4.25 (2H, t, J = 8.0 Hz), 3.96 (3H, s), 3.91 (2H, t, J = 7.8 Hz), 2.28-2.20 (2H, m). 442

¹H-NMR (DMSO-D₆) δ: 8.16- 8.11 (1H, m), 7.97 (1H, s), 7.63-7.59 (1H, m), 7.61 (1H, d, J = 0.4 Hz), 7.31- 7.24 (3H, m), 7.25 (1H, s), 7.24-7.22 (1H, m), 6.85 (1H, d, J = 2.6 Hz), 4.54 (2H, s), 3.96 (3H, s), 2.67 (3H, d, J = 4.6 Hz).

TABLE 1-65 compound No. structural formula NMR 443

¹H-NMR (DMSO-D₆) δ: 7.79- 7.73 (2H, m), 7.61-7.57 (1H, m), 7.48-7.44 (1H, m), 7.32-7.28 (1H, m), 7.26 (1H, br s), 7.18-7.15 (1H, m), 7.11-7.06 (1H, m), 4.19 (1H, t, J = 5.1 Hz), 4.11 (1H, t, J = 5.8 Hz), 3.74 (1H, t, J = 5.4 Hz), 3.66- 3.61 (2H, m), 3.54-3.49 (1H, m), 2.60 (1H, t, J = 7.2 Hz), 2.50-2.45 (1H, m), 2.08 (1.5H, s), 2.06 (1.5H, s). 444

¹H-NMR (DMSO-D₆) δ: 7.78- 7.73 (2H, m), 7.61-7.47 (1H, m), 7.48-7.43 (1H, m), 7.32-7.28 (1H, m), 7.18- 7.16 (1H, m), 7.08 (1H, dd, J = 8.3, 2.3 Hz), 4.16 (2H, t, J = 5.7 Hz), 3.32 (2H, s), 3.01 (2H, t, J = 5.7 Hz), 2.46 (3H, s). 445

¹H-NMR (CDCl₃) δ: 7.69-7.65 (1H, m), 7.59-7.54 (2H, m), 7.47-7.42 (1H, m), 7.32- 7.27 (1H, m), 7.24-7.22 (1H, m), 6.99-6.94 (1H, m), 6.00 (1H, br s), 4.11-4.03 (2H, m), 3.89-3.84 (1H, m), 3.39 (0.5H, br s), 3.35 (0.5H, br s), 2.46-2.28 (3H, m), 1.98-1.85 (1H, m). 446

¹H-NMR (CDCl₃) δ: 7.69-7.65 (1H, m), 7.58-7.54 (2H, m), 7.47-7.42 (1H, m), 7.32- 7.27 (1H, m), 7.24-7.22 (1H, m), 6.99-6.94 (1H, m), 6.00 (1H, br s), 4.10-4.03 (2H, m), 3.89-3.83 (1H, m), 3.40-3.34 (1H, m), 2.47- 2.28 (3H, m), 1.97-1.85 (1H, m). 447

¹H-NMR (CDCl₃) δ: 7.69-7.65 (1H, m), 7.59-7.55 (2H, m), 7.47-7.43 (1H, m), 7.32- 7.27 (1H, m), 7.25-7.23 (1H, m), 7.00-6.96 (1H, m), 4.17-4.12 (1H, m), 4.07- 4.01 (1H, m), 3.94-3.87 (1H, m), 3.16 (0.5H, s), 3.12 (0.5H, s), 2.91 (1.5H, s), 2.90 (1.5H, s), 2.59- 2.48 (1H, m), 2.42-2.33 (1H, m), 2.31-2.20 (1H, m), 2.03-1.93 (1H, m). 448

¹H-NMR (CDCl₃) δ: 7.69-7.65 (1H, m), 7.59-7.55 (2H, m), 7.47-7.43 (1H, m), 7.32- 7.28 (1H, m), 7.25-7.23 (1H, m), 7.00-6.96 (1H, m), 4.18-4.13 (1H, m), 4.07- 4.02 (1H, m), 3.94-3.88 (1H, m), 3.06 (0.5H, s), 3.04 (0.5H, s), 2.92 (1.5H, s), 2.91 (1.5H, s), 2.60- 2.49 (1H, m), 2.43-2.33 (1H, m), 2.31-2.21 (1H, m), 2.03-1.94 (1H, m).

TABLE 1-66 compound No. structural formula NMR 449

¹H-NMR (DMSO-D₆) δ: 12.16 (1H, br s), 7.98 (1H, s), 7.61-7.58 (1H, m), 7.61 (1H, s), 7.31-7.22 (3H, m), 7.22 (1H, s), 7.15-7.12 (1H, m), 6.82 (1H, d, J = 2.6 Hz), 4.06 (2H, t, J = 6.4 Hz), 3.95 (3H, s), 2.40 (2H, t, J = 7.2 Hz), 2.00- 1.92 (2H, m). 450

¹H-NMR (DMSO-D₆) δ: 7.78- 7.74 (2H, m), 7.60-7.57 (1H, m), 7.48-7.44 (1H, m), 7.32-7.28 (1H, m), 7.25- 7.24 (1H, m), 7.16-7.14 (1H, m), 7.10-7.06 (1H, m), 4.86 (1H, t, J = 5.3 Hz), 4.20-4.07 (2H, m), 3.87- 3.79 (1H, m), 3.76-3.68 (1H, m), 3.65-3.59 (1H, m), 3.50-3.36 (2H, m), 2.34- 2.23 (1H, m), 2.20-2.11 (1H, m), 2.03-1.93 (1H, m), 1.84-1.74 (1H, m). 451 (optically active form)

¹H-NMR (CDCl₃) δ: 8.39 (1H, d, J = 7.9 Hz), 7.70-7.67 (1H, m), 7.53-7.48 (1H, m), 7.39-7.35 (1H, m), 7.26- 7.24 (1H, m), 7.16 (1H, d, J = 2.3 Hz), 4.68 (2H, s), 3.83 (3H, s), 2.77 (1H, s). 452 (optically active form)

¹H-NMR (CDCl₃) δ: 8.41-8.38 (1H, m), 7.70-7.67 (1H, m), 7.53-7.49 (1H, m), 7.39- 7.35 (1H, m), 7.27-7.25 (1H, m), 7.17 (1H, d, J = 2.3 Hz), 4.69 (2H, s), 3.84 (3H, s), 2.73 (1H, s). 453

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, s), 7.64-7.58 (1H, m), 7.61 (1H, s), 7.29-7.21 (3H, m), 7.22 (1H, s), 7.16-7.12 (1H, m), 6.82 (1H, d, J = 2.6 Hz), 4.57 (1H, t, J = 5.3 Hz), 4.11 (2H, t, J = 6.6 Hz), 3.95 (3H, s), 3.57 (2H, dt, J = 6.6, 5.3 Hz), 1.93-1.84 (2H, m). 454

¹H-NMR (DMSO-D₆) δ: 12.41 (1H, br s), 7.99 (1H, s), 7.63-7.57 (1H, m), 7.62 (1H, s), 7.31-7.23 (3H, m), 7.24 (1H, s), 7.15-7.12 (1H, m), 6.82 (1H, d, J = 2.3 Hz), 4.25 (2H, t, J = 6.0 Hz), 3.96 (3H, s), 2.73 (2H, t, J = 6.0 Hz). 455

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, s), 7.63-7.56 (1H, m), 7.61 (1H, s), 7.29-7.22 (3H, m), 7.24 (1H, s), 7.14-7.11 (1H, m), 6.80 (1H, d, J = 2.6 Hz), 4.26 (2H, t, J = 6.4 Hz), 3.95 (3H, s), 3.01 (3H, s), 2.86-2.79 (2H, m), 2.85 (3H, s).

TABLE 1-67 compound No. structural formula NMR 456

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, s), 7.62-7.58 (1H, m), 7.61 (1H, d, J = 0.7 Hz), 7.31-7.22 (4H, m), 7.16-7.14 (1H, m), 6.82 (1H, d, J = 2.6 Hz), 4.90 (1H, t, J = 5.6 Hz), 4.06 (2H, t, J = 4.9 Hz), 3.95 (3H, s), 3.73 (2H, dt, J = 5.6, 4.9 Hz). 457

¹H-NMR (DMSO-D₆) δ: 7.95-7.94 (1H, m), 7.61-7.57 (1H, m), 7.59 (1H, d, J = 0.7 Hz), 7.30-7.21 (3H, m), 7.22 (1H, s), 7.14-7.12 (1H, m), 6.81 (1H, d, J = 2.4 Hz), 4.89 (2H, br s), 3.95 (3H, s), 3.00 (3H, s), 2.85 (3H, s). 458

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, d, J = 0.7 Hz), 7.64 (1H, d, J = 0.7 Hz), 7.61-7.57 (1H, m), 7.33-7.22 (3H, m), 7.23 (1H, s), 7.15-7.13 (1H, m), 6.84 (1H, d, J = 2.3 Hz), 4.97 (1H, t, J = 5.3 Hz), 4.25 (2H, t, J = 5.6 Hz), 3.85-3.80 (2H, m), 3.84 (3H, s). 459

¹H-NMR (DMSO-D₆) δ: 7.79-7.74 (2H, m), 7.61-7.57 (1H, m), 7.49-7.44 (1H, m), 7.33-7.28 (1H, m), 7.25 (1H, s), 7.19- 7.16 (1H, m), 7.10 (1H, dd, J = 8.4, 2.4 Hz), 4.30-4.24 (2H, m), 4.19 (2H, t, J = 5.3 Hz), 3.70-3.65 (2H, m), 3.57 (2H, t, J = 5.3 Hz). 460

¹H-NMR (CDCl₃) δ: 7.71-7.68 (1H, m), 7.67-7.65 (1H, m), 7.62 (1H, d ,J = 0.7 Hz), 7.60 (1H, s), 7.35-7.26 (4H, m), 4.37-4.34 (2H, m), 4.13-4.08 (2H, m), 3.03 (1H, s), 2.89 (1H, t, J = 5.9 Hz). 461

¹H-NMR (CDCl₃) δ: 7.78-7.74 (2H, m), 7.47-7.44 (1H, m), 7.41-7.33 (4H, m), 7.29-7.24 (1H, m), 4.96 (1H, br s), 4.38-4.24 (4H, m), 4.18-4.10 (2H, m), 4.08-4.03 (2H, m), 3.47 (1H, br s), 2.37-2.28 (2H, m). 462

¹H-NMR (DMSO-D₆) δ: 12.85 (1H, br s), 7.76-7.72 (2H, m), 7.60-7.57 (1H, m), 7.48-7.43 (1H, m), 7.32-7.28 (1H, m), 7.23 (1H, br s), 7.18-7.15 (1H, m), 7.03-6.99 (1H, m), 4.96 (1.2H, s), 4.80 (0.8H, s), 4.19 (0.8H, s), 4.02 (1.2H, s), 3.07 (1.8H, s), 2.86 (1.2H, s).

TABLE 1-68 compound No. structural formula NMR 463

¹H-NMR (CDCl₃) δ: 7.68-7.63 (1H, m), 7.51-7.46 (1H, m), 7.47 (1H, s), 7.29-7.19 (4H, m), 6.77 (1H, d, J = 2.4 Hz), 3.99 (3H, s), 3.87 (3H, s), 3.24 (1H, br s). 464

¹H-NMR (DMSO-D₆) δ: 7.99 (1H, s), 7.72 (1H, br s), 7.63-7.59 (1H, m), 7.62 (1H, s), 7.31-7.23 (3H, m), 7.28 (1H, s), 7.17-7.13 (1H, m), 6.83 (1H, d, J = 2.4 Hz), 4.23-4.08 (2H, m), 3.96 (3H, s), 3.78-3.67 (1H, m), 3.55-3.45 (1H, m), 2.53-2.42 (3H, m), 2.20- 2.08 (1H, m). 465

¹H-NMR (CDCl₃) δ: 7.73-7.68 (2H, m), 7.51-7.50 (1H, m), 7.36-7.14 (6H, m), 4.57- 4.50 (1H, m), 3.70 (1H, br s), 1.55 (3H, s), 1.54 (3H, s). 466

¹H-NMR (CDCl₃) δ: 7.70-7.65 (2H, m), 7.57 (1H, s), 7.50 (1H, s), 7.42-7.25 (8H, m), 7.22-7.14 (2H, m), 5.39 (2H, s), 2.99 (1H, br s). 467 (optically active form)

H-NMR (DMSO-D₆) δ: 7.97 (1H, s), 7.64-7.59 (2H, m), 7.60 (1H, s), 7.41 (1H, br s), 7.30-7.25 (3H, m), 7.24 (1H, s), 7.23-7.20 (1H, m), 6.84 (1H, d, J = 2.4 Hz), 4.50 (2H, s), 3.96 (3H, s). 468

¹H-NMR (DMSO-D₆) δ: 7.78- 7.75 (2H, m), 7.61-7.57 (1H, m), 7.49-7.44 (1H, m), 7.33-7.28 (1H, m), 7.25 (1H, s), 7.19-7.16 (1H, m), 7.09 (1H, dd, J = 8.4, 2.4 Hz), 4.19 (2H, t, J = 5.4 Hz), 3.39-3.30 (4H, m), 3.23-3.18 (2H, m), 2.29- 2.21 (2H, m). 469

¹H-NMR (DMSO-D₆) δ: 7.79- 7.73 (2H, m), 7.61-7.57 (1H, m), 7.48-7.43 (1H, m), 7.32-7.27 (1H, m), 7.24 (1H, s), 7.18-7.15 (1H, m), 7.09 (1H, dd, J = 8.4, 2.4 Hz), 6.38 (1H, s), 4.15- 4.09 (2H, m), 3.50-3.41 (4H, m), 3.26-3.20 (2H, m).

TABLE 1-69 compound No. structural formula NMR 470

¹H-NMR (DMSO-D₆) δ: 7.78- 7.73 (2H, m), 7.61-7.57 (1H, m), 7.49-7.43 (1H, m), 7.33-7.27 (1H, m), 7.25 (1H, s), 7.19-7.17 (1H, m), 7.10 (1H, dd, J = 8.3, 2.3 Hz), 4.21-4.14 (4H, m), 3.66-3.56 (2H, m), 3.45 (2H, t, J = 6.2 Hz), 1.97- 1.90 (2H, m). 471

¹H-NMR (CDCl₃) δ : 7.67-7.63 (1H, m), 7.59 (1H, s), 7.50 (1H, s), 7.28-7.21 (4H, m), 6.77 (1H, d, J = 2.3 Hz), 4.19 (2H, t, J = 5.4 Hz), 4.01 (3H, s), 3.81-3.68 (2H, m), 3.26 (3H, br s), 3.14 (1H, s), 1.28 (9H, s). 472

¹H-NMR (DMSO-D₆) δ: 8.54 (1H, d, J = 7.9 Hz), 8.24 (1H, d, J = 1.5 Hz), 8.18- 8.16 (1H, m), 7.79-7.76 (1H, m), 7.70-7.65 (1H, m), 7.64 (1H, s), 7.62-7.58 (1H, m), 3.92 (3H, s). 473 (optically active form)

¹H-NMR (CDCl₃) δ: 8.58 (1H, d, J = 7.7 Hz), 8.34 (1H, d, J = 1.3 Hz), 8.30-8.29 (1H, m), 7.78-7.75 (1H, m), 7.60-7.56 (1H, m), 7.52- 7.48 (1H, m), 3.95 (3H, s), 2.84 (1H, s). 474 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, s), 7.62-7.58 (1H, m), 7.61 (1H, s), 7.32-7.24 (3H, m), 7.25 (1H, s), 7.15-7.13 (1H, m), 6.81 (1H, d, J = 2.4 Hz), 4.82- 4.79 (1H, m), 4.65 (2H, s), 4.28-4.22 (1H, m), 4.01- 3.87 (2H, m), 3.96 (3H, s), 3.64 (1H, dd, J = 9.5, 5.3 Hz), 3.54-3.49 (2H, m), 2.74-2.66 (1H, m). 475 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, s), 7.62-7.58 (1H, m), 7.61 (1H, s), 7.30-7.24 (3H, m), 7.25 (1H, s), 7.15-7.13 (1H, m), 6.81 (1H, d, J = 2.4 Hz), 5.76 (1H, d, J = 6.0 Hz), 4.69 (1H, d, J = 14.8 Hz), 4.65 (1H, d, J = 14.8 Hz), 4.54- 4.39 (2H, m), 4.15-4.08 (1H, m), 4.00-3.94 (1H, m), 3.96 (3H, s), 3.67-3.62 (1H, m). 476

¹H-NMR (CDCl₃) δ: 7.80-7.76 (1H, m), 7.72-7.70 (1H, m), 7.38-7.32 (3H, m), 7.27- 7.22 (1H, m), 7.13 (1H, d, J = 1.6 Hz), 7.06 (1H, s), 5.42 (1H, br s), 4.22-4.18 (2H, m), 4.02-3.98 (2H, m), 3.96 (1H, br s), 3.64-3.58 (2H, m), 3.47-3.40 (2H, m), 2.02-1.85 (4H, m).

TABLE 1-70 compound No. structural formula NMR 477 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, s), 7.63 (1H, s), 7.62-7.59 (2H, m), 7.41 (1H, br s), 7.34-7.30 (1H, m), 7.29-7.23 (3H, m), 7.22-7.20 (1H, m), 6.86 (1H, d, J = 2.2 Hz), 4.98 (1H, t, J = 5.2 Hz), 4.51 (2H, s), 4.26 (2H, t, J = 5.6 Hz), 3.83 (2H, dt, J = 5.6, 5.2 Hz). 478

¹H-NMR (DMSO-D₆) δ: 12.17 (1H, s), 8.14 (1H, d, J = 7.7 Hz), 7.67-7.64 (1H, m), 7.56-7.51 (1H, m), 7.43- 7.38 (1H, m), 7.42 (1H, s), 7.17-7.15 (2H, m), 4.09 (2H, t, J = 6.4 Hz), 2.41 (2H, t, J = 7.3 Hz), 2.01- 1.92 (2H, m). 479 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.14 (1H, d, J = 7.7 Hz), 7.66 (1H, d, J = 7.7 Hz), 7.56- 7.52 (1H, m), 7.43-7.38 (1H, m), 7.42 (1H, br s), 7.16 (2H, s), 4.09 (2H, t, J = 6.5 Hz), 2.39 (2H, t, J = 7.3 Hz), 1.99-1.93 (2H, m). 480

¹H-NMR (CDCl₃) δ: 8.23-8.20 (1H, m), 7.70-7.67 (1H, m), 7.51-7.47 (1H, m), 7.38- 7.33 (1H, m), 7.21-7.19 (1H, m), 6.97 (1H, d, J = 2.2 Hz), 4.68 (2H, s), 3.83 (3H, s), 2.78 (1H, s). 481 (optically active form)

¹H-NMR (CDCl₃) δ: 8.23-8.20 (1H, m), 7.70-7.67 (1H, m), 7.52-7.47 (1H, m), 7.38- 7.33 (1H, m), 7.21-7.20 (1H, m), 6.97 (1H, d, J = 2.2 Hz), 4.69 (2H, s), 3.84 (3H, s), 2.75 (1H, s). 482

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, s), 7.63 (1H, s), 7.61-7.56 (1H, m), 7.34- 7.29 (1H, m), 7.28-7.19 (3H, m), 7.15-7.12 (1H, m), 6.83 (1H, d, J = 2.4 Hz), 4.25 (2H, t, J = 5.6 Hz), 4.06 (2H, t, J = 6.4 Hz), 3.82 (2H, t, J = 5.6 Hz), 2.40 (2H, t, J = 7.3 Hz), 2.00-1.93 (2H, m). 483

¹H-NMR (DMSO-D₆) δ: 13.20 (1H, br s), 8.00 (1H, d, J = 0.7 Hz), 7.66-7.61 (2H, m), 7.63 (1H, d, J = 0.7 Hz), 7.42-7.37 (2H, m), 7.36-7.21 (4H, m), 6.07 (2H, s).

TABLE 1-71 compound No. structural formula NMR 484

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, s), 7.64 (1H, s), 7.61-7.58 (1H, m), 7.35- 7.32 (1H, m), 7.28-7.23 (2H, m), 7.24 (1H, s), 7.14-7.12 (1H, m), 6.85 (1H, d, J = 2.3 Hz), 4.98 (1H, t, J = 5.2 Hz), 4.25 (2H, t, J = 5.7 Hz), 4.16 (2H, t, J = 5.2 Hz), 3.85- 3.79 (2H, m), 3.57 (2H, t, J = 5.4 Hz), 3.47 (2H, t, J = 7.3 Hz), 2.22 (2H, t, J = 8.1 Hz), 1.96-1.88 (2H, m). 485

¹H-NMR (DMSO-D₆) δ: 12.44 (1H, br s), 7.98 (1H, s), 7.66-7.60 (2H, m), 7.61 (1H, s), 7.41-7.26 (5H, m), 7.21 (1H, s), 4.43 (2H, t, J = 6.6 Hz), 2.90 (2H, t, J = 6.5 Hz). 486

¹H-NMR (CDCl₃) δ: 7.72-7.67 (2H, m), 7.61 (1H, s), 7.59 (1H, s), 7.36-7.22 (5H, m), 5.76 (1H, br s), 5.33 (1H, br s), 4.55 (2H, t, J = 6.3 Hz), 2.95 (1H, br s), 2.91 (2H, t, J = 6.1 Hz). 487

¹H-NMR (CDCl₃) δ: 7.72-7.67 (2H, m), 7.54 (1H, s), 7.52 (1H, s), 7.35-7.21 (5H, m), 5.69 (1H, br s), 4.51 (2H, t, J = 6.3 Hz), 3.26 (1H, br s), 2.82 (2H, t, J = 6.3 Hz), 2.77 (3H, d, J = 4.6 Hz). 488

¹H-NMR (CDCl₃) δ: 7.72-7.66 (2H, m), 7.59 (1H, s), 7.55 (1H, s), 7.34-7.23 (5H, m), 4.53 (2H, t, J = 6.5 Hz), 3.22 (1H, br s), 3.01 (3H, s), 3.00-2.96 (2H, m), 2.95 (3H, s). 489

¹H-NMR (CDCl₃) δ: 7.68-7.64 (1H, m), 7.58 (1H, s), 7.50 (1H, s), 7.25-7.20 (4H, m), 6.77 (1H, d, J = 1.6 Hz), 4.29-4.17 (2H, m), 4.01 (3H, s), 3.80-3.72 (2H, m), 3.68 (1H, t, J = 7.2 Hz), 3.53-3.40 (2H, m), 3.42 (1H, br s), 3.24 (3H, br s), 1.27 (3H, s), 1.24 (3H, s). 490

¹H-NMR (DMSO-D₆) δ: 7.79- 7.74 (2H, m), 7.61-7.57 (1H, m), 7.49-7.44 (1H, m), 7.33-7.28 (1H, m), 7.24 (1H, s), 7.19-7.16 (1H, m), 7.10 (1H, dd, J = 8.4, 2.4 Hz), 4.20 (2H, t, J = 5.6 Hz), 4.05 (2H, s), 3.82 (2H, t, J = 5.1 Hz), 3.74- 3.69 (2H, m), 3.54-3.50 (2H, m).

TABLE 1-72 compound No. structural formula NMR 491

¹H-NMR (DMSO-D₆) δ: 13.15 (1H, br s), 8.01 (1H, br s), 7.67 (1H, br s), 7.61- 7.58 (1H, m), 7.28-7.24 (2H, m), 7.22 (1H, s), 7.20-7.17 (1H, m), 7.15- 7.13 (1H, m), 6.86 (1H, d, J = 2.4 Hz), 4.16 (2H, t, J = 5.4 Hz), 3.57 (2H, t, J = 5.5 Hz), 3.47 (2H, t, J = 7.2 Hz), 2.22 (2H, t, J = 8.0 Hz), 1.96-1.88 (2H, m). 492

¹H-NMR (DMSO-D₆) δ: 7.93 (1H, s), 7.64-7.58 (1H, m), 7.60 (1H, s), 7.44-7.41 (1H, m), 7.36-7.25 (3H, m), 7.14 (1H, s), 7.12 (1H, d, J = 7.0 Hz), 4.95 (1H, t, J = 5.1 Hz), 4.25 (2H, t, J = 5.7 Hz), 3.83 (2H, dt, J = 5.7, 5.1 Hz), 2.39 (3H, s). 493

¹H-NMR (CDCl₃) δ: 7.77 (1H, s), 7.73-7.69 (2H, m), 7.64 (1H, s), 7.38-7.25 (5H, m), 6.42 (1H, br s), 5.52 (1H, br s), 4.92 (2H, s), 2.79 (1H, br s). 494

¹H-NMR (CDCl₃) δ: 7.76 (1H, s), 7.73-7.70 (2H, m), 7.61 (1H, s), 7.39-7.25 (5H, m), 6.42 (1H, br s), 4.90 (2H, s), 2.89 (3H, d, J = 4.9 Hz), 2.84 (1H, br s). 495

¹H-NMR (CDCl₃) δ: 7.70-7.66 (2H, m), 7.63 (1H, s), 7.61 (1H, s), 7.45-7.42 (1H, m), 7.35-7.27 (4H, m), 5.09 (1H, d, J = 16.0 Hz), 5.03 (1H, d, J = 16.0 Hz), 3.14 (3H, s), 3.03 (3H, s), 2.99 (1H, br s). 496

¹H-NMR (DMSO-D₆) δ: 7.96 (1H, s), 7.62 (1H, s), 7.61-7.57 (1H, m), 7.33- 7.29 (1H, m), 7.28-7.23 (3H, m), 7.15-7.12 (1H, m), 6.82 (1H, d, J = 2.4 Hz), 4.97 (1H, t, J = 5.2 Hz), 4.66 (2H, s), 4.25 (4H, t, J = 5.7 Hz), 3.91 (2H, t, J = 7.7 Hz), 3.82 (2H, dt, J = 5.7, 5.2 Hz), 2.28-2.21 (2H, m). 497

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, s), 7.63 (1H, s), 7.61-7.58 (1H, m), 7.33- 7.29 (1H, m), 7.28-7.24 (3H, m), 7.15-7.12 (1H, m), 6.82 (1H, d, J = 2.6 Hz), 5.77 (1H, d, J = 5.5 Hz), 4.98 (1H, t, J = 5.2 Hz), 4.72-4.64 (2H, m), 4.52- 4.40 (2H, m), 4.25 (2H, t, J = 5.5 Hz), 4.14-4.08 (1H, m), 4.00-3.94 (1H, m), 3.82 (2H, dt, J = 5.5, 5.2 Hz), 3.67-3.61 (1H, m).

TABLE 1-73 compound No. structural formula NMR 498

¹H-NMR (DMSO-D₆) δ: 7.83 (2H, br s), 7.61-7.57 (1H, m) , 7.29-7.12 (5H, m), 6.84 (1H, d, J = 2.4 Hz), 4.06 (2H, t, J = 6.4 Hz), 2.40 (2H, t, J = 7.3 Hz), 2.00- 1.92 (2H, m). 499

¹H-NMR (CDCl₃) δ: 7.69-7.64 (1H, m), 7.52 (1H, s), 7.47 (1H, s), 7.25-7.20 (4H, m), 6.78-6.76 (1H, m), 4.25- 4.11 (2H, m), 4.06-3.89 (2H, m), 3.98 (3H, s), 3.68-3.52 (2H, m), 3.10 (3H, s), 2.11 (3H, s). 500

¹H-NMR (CDCl₃) δ: 7.70-7.65 (1H, m), 7.52 (1H, s), 7.48 (1H, s), 7.25-7.21 (4H, m), 6.79-6.76 (1H, m), 4.27 (1H, dd, J = 20.9, 4.2 Hz), 4.21-4.12 (1H, m), 4.06- 3.89 (2H, m), 3.99 (3H, s), 3.69-3.53 (2H, m), 3.11 (3H, s), 2.12 (3H, s). 501

¹H-NMR (CDCl₃) δ: 7.68-7.64 (1H, m), 7.56 (1H, s), 7.50 (1H, s), 7.25-7.22 (4H, m), 6.78-6.75 (1H, m), 4.43 (1H, br s), 4.26-4.21 (2H, m), 4.02-3.99 (3H, m), 3.87-3.77 (2H, m), 3.37- 3.21 (3H, m), 1.58-1.56 (6H, m). 502

¹H-NMR (DMSO-D₆) δ: 8.09 (1H, br s), 7.87-7.84 (1H, m), 7.72 (1H, br s), 7.63- 7.59 (1H, m), 7.46-7.40 (1H, m), 7.35-7.29 (2H, m), 7.23-7.21 (1H, m), 7.06- 7.04 (1H, m), 4.22-4.16 (2H, m), 3.61-3.56 (2H, m), 3.51-3.45 (2H, m), 2.27- 2.20 (2H, m), 1.98-1.89 (2H, m). 503

¹H-NMR (DMSO-D₆) δ: 7.82 (2H, br s), 7.63 (1H, br s), 7.61-7.58 (1H, m), 7.41 (1H, br s), 7.28-7.16 (5H, m), 6.86 (1H, d, J = 2.4 Hz), 4.51 (2H, s). 504 (optically active form)

¹H-NMR (DMSO-D₆) δ: 12.26 (1H, br s), 7.99-7.96 (1H, m), 7.62-7.57 (2H, m), 7.29-7.20 (4H, m), 7.15- 7.12 (1H, m), 6.83-6.80 (1H, m), 4.05 (2H, t, J = 6.1 Hz), 3.95 (3H, s), 2.39 (2H, t, J = 7.0 Hz), 2.00- 1.92 (2H, m).

TABLE 1-74 compound No. structural formula NMR 505

¹H-NMR (DMSO-D₆) δ: 8.02 (1H, d, J = 1.2 Hz), 7.67 (1H, d, J = 1.2 Hz), 7.65- 7.61 (1H, m), 7.41-7.36 (3H, m), 7.35-7.27 (2H, m), 7.18-7.14 (1H, m), 4.99- 4.95 (1H, m), 4.24 (2H, t, J = 4.9 Hz), 3.84-3.78 (2H, m). 506

¹H-NMR (CDCl₃) δ: 7.76-7.73 (1H, m), 7.72-7.67 (2H, m), 7.66-7.63 (1H, m), 7.36- 7.22 (4H, m), 6.38 (1H, s), 5.57 (1H, s), 4.93-4.88 (2H, m), 2.98 (1H, br s). 507

¹H-NMR (CDCl₃) δ: 7.74-7.73 (1H, m), 7.71-7.67 (1H, m), 7.61-7.61 (1H, m), 7.54- 7.51 (1H, m), 7.32-7.19 (3H, m), 7.11-7.09 (1H, m), 6.41 (1H, br s), 5.58 (1H, br s), 4.90-4.88 (2H, m), 2.97 (1H, br s), 2.45-2.42 (3H, m). 508

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, d, J = 0.7 Hz), 7.64 (1H, d, J = 0.9 Hz), 7.60- 7.55 (1H, m), 7.57 (1H, br s), 7.42-7.37 (1H, m), 7.32 (1H, br s), 7.27-7.22 (2H, m), 7.21 (1H, s), 7.14-7.11 (1H, m), 6.84 (1H, d, J = 2.4 Hz), 4.87 (2H, s), 4.10 (2H, t, J = 6.8 Hz), 1.97- 1.91 (3H, m), 1.72-1.53 (14H, m). 509

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, d, J = 0.4 Hz), 7.64 (1H, d, J = 0.7 Hz), 7.60- 7.57 (1H, m), 7.32-7.22 (3H, m), 7.20 (1H, s), 7.13-7.11 (1H, m), 6.83 (1H, d, J = 2.4 Hz), 4.97 (1H, t, J = 5.2 Hz), 4.25 (2H, t, J = 5.6 Hz), 4.10 (2H, t, J = 6.8 Hz), 3.84- 3.80 (2H, m), 1.97-1.91 (3H, m), 1.71-1.52 (14H, m). 510

¹H-NMR (DMSO-D₆) δ: 9.37 (1H, s), 8.95 (2H, br s), 7.65-7.62 (1H, m), 7.37 (1H, br s), 7.31-7.21 (3H, m), 7.04-7.04 (1H, m), 6.61 (1H, dd, J = 6.7, 1.0 Hz), 4.11 (2H, t, J = 6.5 Hz), 2.40 (2H, t, J = 7.3 Hz), 2.01-1.95 (2H, m). 511

¹H-NMR (DMSO-D₆) δ: 8.20- 8.16 (1H, m), 7.96 (1H, d, J = 0.7 Hz), 7.66-7.60 (2H, m), 7.62 (1H, d, J = 0.9 Hz), 7.46-7.43 (1H, m), 7.42-7.27 (4H, m), 7.22 (1H, s), 4.87 (2H, s), 3.20-3.13 (2H, m), 1.08 (3H, t, J = 7.2 Hz).

TABLE 1-75 compound No. structural formula NMR 512

¹H-NMR (DMSO-D₆) δ: 8.13- 8.08 (1H, m), 7.95 (1H, d, J = 2.6 Hz), 7.64-7.59 (1H, m), 7.61 (1H, d, J = 2.6 Hz), 7.45-7.40 (2H, m), 7.34-7.25 (2H, m), 7.19- 7.12 (2H, m), 4.90-4.86 (2H, m), 2.70-2.67 (3H, m), 2.41-2.37 (3H, m). 513

¹H-NMR (DMSO-D₆) δ: 8.13- 8.07 (1H, m), 8.06 (1H, d, J = 2.6 Hz), 7.70 (1H, d, J = 2.6 Hz), 7.68-7.64 (1H, m), 7.61-7.58 (1H, m), 7.51-7.47 (1H, m), 7.45- 7.43 (1H, m), 7.42-7.31 (3H, m), 4.91-4.87 (2H, m), 2.70-2.66 (3H, m). 514

¹H-NMR (DMSO-D₆) δ: 8.12- 8.08 (1H, m), 7.95 (1H, d, J = 0.7 Hz), 7.66-7.60 (2H, m), 7.61 (1H, d, J = 0.7 Hz), 7.46-7.26 (5H, m), 7.22 (1H, s), 4.85 (2H, s), 3.93-3.85 (1H, m), 1.11 (6H, d, J = 6.6 Hz). 515

¹H-NMR (DMSO-D₆) δ: 8.13- 8.08 (1H, m), 8.04 (1H, d, J = 0.9 Hz), 7.68 (1H, d, J = 0.9 Hz), 7.67-7.63 (1H, m), 7.49-7.45 (1H, m), 7.43-7.39 (2H, m), 7.37- 7.29 (2H, m), 7.18 (1H, dd, J = 9.9, 2.4 Hz), 4.89 (2H, s), 2.68 (3H, d, J = 4.4 Hz). 516

¹H-NMR (DMSO-D₆) δ: 13.18 (1H, br s), 8.40 (1H, s), 8.23 (1H, d, J = 7.9 Hz), 8.10 (1H, s), 7.84 (1H, d, J = 1.4 Hz), 7.80-7.78 (1H, m) , 7.72-7.69 (1H, m), 7.61-7.56 (1H, m), 7.49- 7.45 (2H, m), 5.00 (2H, s). 517

¹H-NMR (DMSO-D₆) δ: 12.42 (1H, s), 8.41 (1H, s), 8.22 (1H, d, J = 7.9 Hz), 8.06 (1H, d, J = 0.7 Hz), 7.82 (1H, d, J = 1.6 Hz), 7.80- 7.78 (1H, m), 7.72-7.69 (1H, m), 7.60-7.55 (1H, m), 7.49-7.44 (1H, m), 7.45 (1H, s), 4.35 (2H, t, J = 6.7 Hz), 2.86 (2H, t, J = 6.8 Hz). 518

¹H-NMR (DMSO-D₆) δ: 8.32 (1H, s), 8.15 (1H, br s), 7.98 (1H, d, J = 0.8 Hz), 7.91 (1H, d, J = 7.5 Hz), 7.84-7.81 (1H, m), 7.75 (1H, br s), 7.69 (1H, d, J = 1.9 Hz), 7.67-7.63 (1H, m), 7.49-7.43 (1H, m), 7.40-7.34 (1H, m), 7.31 (1H, s), 3.89 (3H, s).

TABLE 1-76 compound No. structural formula NMR 519

¹H-NMR (CDCl₃) δ: 8.27 (1H, d, J = 7.9 Hz), 7.72-7.68 (1H, m), 7.53-7.47 (1H, m), 7.44-7.42 (1H, m), 7.40- 7.35 (1H, m), 7.26-7.25 (1H, m), 2.76 (1H, s), 2.41 (3H, s). 520 (optically active form)

¹H-NMR (CDCl₃) δ: 8.28 (1H, d, J = 7.7 Hz), 7.72-7.68 (1H, m), 7.53-7.48 (1H, m), 7.44-7.42 (1H, m), 7.41- 7.36 (1H, m), 7.27-7.25 (1H, m), 2.69 (1H, s), 2.41 (3H, s). 521

¹H-NMR (DMSO-D₆) δ: 8-34 (1H, s), 8.22 (1H, d, J = 7.7 Hz), 8.05 (1H, d, J = 0.7 Hz), 7.81 (1H, d, J = 1.5 Hz), 7.79-7.76 (1H, m), 7.72-7.68 (1H, m), 7.60- 7.55 (1H, m), 7.49-7.43 (1H, m), 7.44 (1H, s), 7.42 (1H, br s), 6.91 (1H, br s), 4.33 (2H, t, J = 6.8 Hz), 2.67 (2H, t, J = 6.9 Hz). 522

¹H-NMR (CDCl₃) δ: 7.71-7.66 (2H, m), 7.64 (1H, d, J = 0.7 Hz), 7.51 (1H, d, J = 0.7 Hz), 7.36-7.22 (5H, m), 3.06 (1H, br s), 2.30-2.25 (3H, m), 2.24-2.22 (6H, m), 1.82-1.78 (6H, m). 523

¹H-NMR (CDCl₃) δ: 7.72-7.66 (2H, m), 7.64 (1H, d, J = 0.7 Hz), 7.53-7.50 (1H, m), 7.36-7.22 (5H, m), 3.06- 3.00 (1H, br m), 1.67 (9H, s). 524

¹H-NMR (CDCl₃) δ: 7.72-7.67 (2H, m), 7.51-7.49 (1H, m), 7.47 (1H, s), 7.36-7.19 (5H, m), 3.99 (2H, s), 3.10 (1H, s), 1.04 (9H, br s). 525

¹H-NMR (CDCl₃) δ: 8.30-8.26 (1H, m), 7.74-7.70 (1H, m), 7.56-7.50 (1H, m), 7.44- 7.35 (2H, m), 7.23-7.18 (1H, m), 2.83-2.81 (1H, m).

TABLE 1-77 compound No. structural formula NMR 526 (optically active form)

¹H-NMR (CDCl₃) δ: 8.27 (1H, d, J = 7.7 Hz), 7.73-7.70 (1H, m), 7.55-7.50 (1H, m), 7.43-7-35 (2H, m), 7.20 (1H, dd, J = 8.6, 2.2 Hz), 2.76 (1H, s). 527

¹H-NMR (CDCl₃) δ: 7.74-7.69 (2H, m), 7.51 (1H, s), 7.46 (1H, s), 7.36-7.28 (2H, m), 7.24-7.21 (3H, m), 6.11 (1H, br s), 4.30 (2H, dd, J = 6.2, 4.9 Hz), 3.77-3.72 (2H, m), 3.54 (1H, br s), 1.98 (3H, s). 528

¹H-NMR (DMSO-D₆) δ: 8.42 (1H, d, J = 0.7 Hz), 8.14 (1H, br s), 7.98 (1H, d, J = 0.7 Hz), 7.93-7.90 (1H, m), 7.87-7.85 (1H, m), 7.75 (1H, br s), 7.72 (1H, d, J = 1.6 Hz), 7.67-7-63 (1H, m), 7.49-7.44 (1H, m), 7.40-7.35 (1H, m), 7.31 (1H, s), 4.58-4.48 (1H, m), 1.47 (3H, s), 1.46 (3H, s). 529 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.94 (1H, d, J = 0.9 Hz), 7.63- 7.58 (1H, m), 7.60 (1H, d, J = 0.7 Hz), 7.44-7.41 (1H, m), 7.36-7.33 (1H, m), 7.32-7.25 (2H, m), 7.16 (1H, s), 7.12 (1H, dd, J = 1.7, 0.8 Hz), 4.97 (1H, t, J = 5.3 Hz), 4.25 (2H, t, J = 5.6 Hz), 3.82 (2H, dt, J = 5.3, 5.6 Hz), 2.38 (3H, s) . 530

¹H-NMR (DMSO-D₆) δ: 8.38 (1H, s), 8.15 (1H, br s), 7.98 (1H, s), 7.91 (1H, d, J = 7.7 Hz), 7.85-7.83 (1H, m), 7.75 (1H, br s), 7.70 (1H, d, J = 1.6 Hz), 7.66- 7.64 (1H, m), 7.49-7.44 (1H, m), 7.40-7.35 (1H, m), 7.31 (1H, s), 4.17 (2H, q, J = 7.3 Hz), 1.42 (3H, t, J = 7.2 Hz). 531 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.03 (1H, d, J = 0.7 Hz), 7.68 (1H, d, J = 0.7 Hz), 7.66- 7.63 (1H, m), 7.42-7.38 (3H, m), 7.36-7.29 (2H, m), 7.18 (1H, dd, J = 10.0, 2.6 Hz), 4.99 (1H, t, J = 5.3 Hz), 4.26 (2H, t, J = 5.6 Hz), 3.82 (2H, dt, J = 5.6, 5.3 Hz). 532 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.94 (1H, d, J = 0.7 Hz), 7.64- 7.59 (1H, m), 7.60 (1H, d, J = 0.7 Hz), 7.57 (1H, br s), 7.46-7.43 (2H, m), 7.32-7.24 (2H, m), 7.32 (1H, br s), 7.17 (1H, s), 7.14 (1H, dd, J = 1.5, 0.9 Hz), 4.88 (2H, s), 2.40 (3H, s).

TABLE 1-78 compound No. structural formula NMR 533 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.12- 8.06 (1H, m), 7.95 (1H, d, J = 0.7 Hz), 7.64-7.59 (1H, m), 7.61 (1H, d, J = 0.7 Hz), 7.45-7.39 (2H, m), 7.33-7.25 (2H, m), 7.17 (1H, s), 7.13 (1H, d, J = 0.7 Hz), 4.88 (2H, s), 2.68 (3H, d, J = 4.6 Hz), 2.39 (3H, s). 534 (optically active form)

¹H-NMR (CDCl₃) δ: 7.74 (1H, s), 7.72-7.68 (1H, m), 7.62 (1H, s), 7.46-7.40 (1H, m), 7.34-7.19 (3H, m), 7.01 (1H, dd, J = 9.4, 2.6 Hz), 6.40 (1H, s), 4.88 (2H, s), 3.06 (1H, s), 2.88 (3H, br s). 535

¹H-NMR (CDCl₃) δ: 7.75-7.69 (2H, m), 7.62 (0.2H, s), 7.56 (0.8H, s), 7.45 (0.2H, s), 7.41 (0.8H, s), 7.36- 7.20 (5H, m), 4.39-4.32 (2H, m), 3.87-3.79 (2H, m), 2.96 (0.8H, s), 2.82 (2.2H, s), 2.04 (2.2H, s), 1.83 (0.8H, s). 536

¹H-NMR (DMSO-D₆) δ: 8.33- 8.31 (1H, m), 8.16 (1H, br s), 8.01-7.99 (1H, m), 7.94-7.90 (1H, m), 7.86- 7.83 (1H, m), 7.76 (1H, br s), 1.12-1.69 (1H, m), 7.68-7.63 (1H, m), 7.50- 7.44 (1H, m), 7.41-7.35 (1H, m), 7.33 (1H, br s), 4.95 (1H, br s), 4.21-4.16 (2H, m), 3.82-3.76 (2H, m). 537 (optically active form)

¹H-NMR (CDCl₃) δ: 7.70-7.67 (1H, m), 7.54 (1H, s), 7.53 (1H, s), 7.42-7.38 (1H, m), 7.30-7.19 (3H, m), 6.98 (1H, dd, J = 9.4, 2.5 Hz), 4.30 (2H, t, J = 6.7 Hz), 2.42 (2H, t, J = 7.1 Hz), 2.27-2.20 (2H, m). 538 (optically active form)

¹H-NMR (CDCl₃) δ: 7.69-7.63 (1H, m), 7.58-7.54 (2H, m), 7.52-7.49 (1H, m), 7.25- 7.14 (3H, m), 7.07-7.05 (1H, m), 4.48 (2H, t, J = 6.2 Hz), 3.00 (2H, t, J = 6.2 Hz), 2.41 (3H, s). 539 (optically active form)

¹H-NMR (CDCl₃) δ: 7.70-7.65 (1H, m), 7.55 (1H, s), 7.52-7.49 (2H, m), 7.29- 7.20 (3H, m), 7.09-7.07 (1H, m), 4.31 (2H, t, J = 6.6 Hz), 2.45-2.39 (2H, m), 2.42 (3H, s), 2.28-2.20 (2H, m).

TABLE 1-79 compound No. structural formula NMR 540 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, s), 7.62 (1H, d, J = 0.7 Hz), 7.61-7.58 (1H, m), 7.29-7.23 (3H, m), 7.21 (1H, s), 7.14-7.11 (1H, m), 6.83 (1H, d, J = 2.4 Hz), 4.35 (1H, s), 4.09 (2H, t, J = 7.2 Hz), 3.96 (3H, s), 2.13-2.07 (2H, m), 1.61 (2H, t, J = 6.8 Hz), 1.57- 1.43 (12H, m). 541 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, d, J = 0.9 Hz), 7.64 (1H, d, J = 0.9 Hz), 7.60- 7.56 (2H, m), 7.41-7.38 (1H, m), 7.32 (1H, br s), 7.26-7.22 (2H, m), 7.21 (1H, s), 7.13-7.12 (1H, m), 6-84 (1H, d, J = 2.4 Hz), 4.87 (2H, s), 4.09 (2H, t, J = 6.9 Hz), 3.57 (1H, s), 2.12-2.07 (2H, m), 1.61 (2H, t, J = 7.2 Hz), 1.56- 1.42 (12H, m). 542 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, d, J = 0.7 Hz), 7.64 (1H, d, J = 0.7 Hz), 7.61- 7.56 (1H, m), 7.33-7.28 (1H, m), 7.28-7.22 (2H, m), 7.21 (1H, s), 7.13-7.11 (1H, m), 6.83 (1H, d, J = 2.6 Hz), 4.97 (1H, t, J = 5.3 Hz), 4.36 (1H, s), 4.25 (2H, t, J = 5.7 Hz), 4.09 (2H, t, J = 7.1 Hz), 3.82 (2H, dt, J = 5.3, 5.7 Hz), 2.12-2.07 (2H, m), 1.60 (2H, t, J = 7.0 Hz), 1.56- 1.42 (13H, m) . 543 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.06 (1H, d, J = 0.7 Hz), 7.68 (1H, d, J = 0.9 Hz), 7.66- 7.62 (1H, m), 7.43-7.38 (1H, m), 7.36-7.28 (4H, m), 7.17 (1H, dd, J = 10.0, 2.6 Hz), 4.43 (2H, t, J = 6.6 Hz), 2.91 (2H, t, J = 6.6 Hz) . 544 (optically active form)

¹H-NMR (CDCl₃) δ: 7.70-7.67 (1H, m), 7.62 (1H, d, J = 0.7 Hz), 7.57 (1H, d, J = 0.7 Hz), 7.42-7.38 (1H, m), 7.31-7.20 (3H, m), 7.00 (1H, dd, J = 9.5, 2.4 Hz), 4.17 (2H, s), 3.47 (1H, br s), 2.98 (1H, br s), 1.74- 1.25 (10H, m). 545 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.05 (1H, d, J = 0.7 Hz), 7.67- 7.63 (2H, m), 7.42-7.38 (2H, m), 7.35-7.30 (3H, m), 7.21-7.16 (1H, m), 4.47- 4.43 (1H, m), 4.17-4.09 (1H, m), 3.20-3.13 (1H, m), 3.09-3.02 (1H, m), 2.04- 1.71 (6H, m), 1.45-1.22 (3H, m) .

TABLE 1-80 compound No. structural formula NMR 546 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.99 (1H, d, J = 0.7 Hz), 7.64- 7.58 (1H, m), 7.60 (1H, s), 7.43-7.40 (1H, m), 7.32- 7.23 (3H, m), 7.16 (1H, d, J = 2.2 Hz), 7.14-7.13 (1H, m), 4.70-4.65 (1H, m), 4.57-4.50 (1H, m), 3.51- 3.37 (2H, m), 2.48-2.39 (1H, m), 2.38 (3H, s), 2.21-2.03 (2H, m), 1.99- 1.89 (1H, m), 1.88-1.78 (1H, m), 1.74-1.63 (1H, m), 1.57-1.47 (1H, m). 547

¹H-NMR (DMSO-D₆) δ: 7.87 (1H, d, J = 0.7 Hz), 7.67- 7.60 (2H, m), 7.59 (1H, d, J = 0.7 Hz), 7.41-7.22 (6H, m), 4.47 (1H, s), 3.96 (2H, s), 2.16-2.12 (2H, m), 1.60-1.41 (12H, m). 548 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.09 (1H, s), 7.67 (1H, s), 7.66-7.62 (1H, m), 7.41- 7.37 (2H, m), 7.36-7.27 (3H, m), 7.20 (1H, dd, J = 10.0, 2.5 Hz), 4.71-4.66 (1H, m), 4.58-4.51 (1H, m), 3.51-3.38 (2H, m), 2.48- 2.37 (1H, m), 2.21-2.04 (2H, m), 1.99-1.89 (1H, m), 1.88-1.78 (1H, m), 1.74- 1.63 (1H, m), 1.57-1.47 (1H, m). 549 (optically active form)

¹H-NMR (DMSO-D₆) δ: 12.43 (1H, br s), 8.12 (1H, s), 7.69 (1H, d, J = 0.9 Hz), 7.66-7.62 (1H, m), 7.42- 7.38 (2H, m), 7.36-7.31 (2H, m), 7.27-7.24 (1H, m), 7.19 (1H, dd, J = 9.9, 2.6 Hz), 5.00-4.94 (1H, m), 3.28-3.19 (1H, m), 2.27- 2.05 (3H, m), 1.94-1.74 (3H, m). 550 (optically active form)

¹H-NMR (DMSO-D₆) δ: 13.17 (1H, br s), 7.97 (1H, d, J = 0.7 Hz), 7.63-7.60 (1H, m), 7.61 (1H, d, J = 0.7 Hz), 7.45-7.43 (1H, m), 7.38-7.34 (1H, m), 7.32- 7.27 (1H, m), 7.26-7.22 (1H, m), 7.17 (1H, s), 7.14-7.12 (1H, m), 5.06 (2H, s), 2.39 (3H, s). 551 (optically active form)

¹H-NMR (DMSO-D₆) δ: 13.22 (1 H, br s), 8.07 (1H, d, J = 0.7 Hz), 7.69 (1H, d, J = 0.7 Hz), 7.66-7.62 (1H, m), 7.43-7.38 (3H, m), 7.36- 7.31 (1H, m), 7.30-7.25 (1H, m), 7.18 (1H, dd, J = 9.9, 2.4 Hz), 5.07 (2H, s).

TABLE 1-81 compound No. structural formula NMR 552 (optically active form)

¹H-NMR (CDCl₃) δ: 7.70-7.66 (1H, m), 7.43 (1H, s), 7.30 (1H, d, J = 0.7 Hz), 7.25- 7.14 (3H, m), 7.12-7.09 (1H, m), 6.70 (1H, d, J = 2.6 Hz), 4.05-3.93 (2H, m), 3.90 (3H, s), 2.37 (2H, t, J = 6.6 Hz), 1.88-1.73 (4H, m) . 553 (optically active form)

¹H-NMR (DMSO-D₆) δ: 12.17 (1H, br s), 8.05 (1H, d, J = 0.7 Hz), 7.62 (1H, d, J = 0.7 Hz), 7.61-7.58 (1H, m), 7.31-7.19 (4H, m), 7.16- 7.13 (1H, m), 6.85 (1H, d, J = 2.3 Hz), 4.64-4.57 (1H, m), 4.07 (2H, t, J = 6.4 Hz), 2.41 (2H, t, J = 7.3 Hz), 2.01-1.94 (2H, m), 1.52 (3H, d, J = 6.5 Hz), 1.51 (3H, d, J = 6.5 Hz). 554 (optically active form)

¹H-NMR (DMSO-D₆) δ: 12.16 (1H, br s), 8.02 (1H, d, J = 0.7 Hz), 7.61 (1H, d, J = 0.7 Hz), 7.61-7.58 (1H, m), 7.30-7.20 (4H, m), 7.13 (1H, d, J = 1.9 Hz), 6.83 (1H, d, J = 2.6 Hz), 4.24 (2H, q, J = 7.3 Hz), 4.06 (2H, t, J = 6.4 Hz), 2.40 (2H, t, J = 7.3 Hz), 2.00- 1.93 (2H, m), 1.46 (3H, t, J = 7.3 Hz). 555

¹H-NMR (DMSO-D₆) δ: 7.88 (1H, d, J = 7.9 Hz), 7.86 (1H, d, J = 7.7 Hz), 7.66- 7.62 (1H, m), 7.53-7.47 (2H, m), 7.41-7.35 (2H, m), 7.28 (1H, s), 3.72 (3H, s), 2.26 (3H, s), 2.17 (3H, s). 556

¹H-NMR (DMSO-D₆) δ: 7.87- 7.84 (1H, m), 7.83-7.82 (1H, m), 7.79-7.77 (1H, m), 7.72-7.67 (1H, m), 7.58- 7.53 (1H, m), 7.48-7.43 (1H, m), 7.35 (1H, s), 5.56 (1H, t, J = 5.5 Hz), 4.95- 4.85 (2H, m), 4.39-4.24 (2H, m), 4.16-3.99 (2H, m), 2.34-2.25 (2H, m). 557

¹H-NMR (DMSO-D₆) δ: 7.95 (1H, s), 7.66-7.56 (3H, m), 7.35-7.28 (3H, m), 7.22- 7.18 (2H, m), 5.35 (1H, t, J = 5.7 Hz), 4.57 (2H, d, J = 5.7 Hz), 3.96 (3H, s). 558

¹H-NMR (DMSO-D₆) δ: 12.25 (1H, br s), 7.94 (1H, d, J = 0.5 Hz), 7.58 (1H, d, J = 0.7 Hz), 7.57-7.54 (1H, m), 7.27-7.15 (4H, m), 7.11 (1H, s), 6.77 (1H, d, J = 2.3 Hz), 3.94 (3H, s), 3.77-3.69 (2H, m), 2.90- 2.81 (2H, m), 2.48-2.40 (1H, m), 1.96-1.88 (2H, m), 1.70-1.59 (2H, m).

TABLE 1-82 compound No. structural formula NMR 559

¹H-NMR (DMSO-D₆) δ: 7.72- 7.67 (1H, m), 7.63 (1H, d, J = 7.2 Hz), 7.57 (1H, d, J = 7.9 Hz), 7.50-7.33 (5H, m), 7.23-7.19 (1H, m), 6.29-6.28 (1H, m), 5.30 (2H, s), 3.62 (1H, br s). 560

¹H-NMR (CDCl₃) δ: 7.90-7.86 (2H, m), 7.77-7.72 (2H, m), 7.65 (1H, d, J = 8.3 Hz), 7.62-7.59 (1H, m), 7.54 (1H, d, J = 1.5 Hz), 7.51- 7.45 (1H, m), 7.41-7.35 (1H, m), 6.40 (1H, dd, J = 2.4, 1.7 Hz), 3.86 (1H, s). 561 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.90- 8.82 (2H, m), 8.29-8.16 (1H, m), 7.90-7.75 (1H, m), 7.63 (1H, d, J = 6.4 Hz), 7.31-7.13 (5H, m), 7.01- 7.00 (1H, m), 6.62 (1H, d, J = 7.9 Hz), 4.10 (2H, t, J = 6.4 Hz), 2.41 (2H, t, J = 7.2 Hz), 1.98 (2H, t, J = 7.0 Hz). 562

¹H-NMR (DMSO-D₆) δ: 8.91 (1H, d, J = 2.1 Hz), 8.40 (1H, s), 8.14 (1H, d, J = 1.4 Hz), 8.07 (1H, s), 7.89-7.86 (1H, m), 7.74- 7.71 (1H, m), 7.62-7.58 (1H, m), 7.54-7.49 (1H, m), 7.50 (1H, s), 3.90 (3H, s). 563

¹H-NMR (DMSO-D₆) δ: 8.92 (1H, d, J = 1.8 Hz), 8.41 (1H, s), 8.16-8.14 (1H, m), 8.09 (1H, s), 7.89-7.86 (1H, m), 7.74-7.71 (1H, m), 7.62-7.58 (1H, m), 7.54- 7.48 (1H, m), 7.50 (1H, s), 4.95 (1H, t, J = 5.3 Hz), 4.19 (2H, t, J = 5.5 Hz), 3.79 (2H, dt, J = 5.5, 5.3 Hz). 564

¹H-NMR (DMSO-D₆) δ: 9.90 (1H, s), 7.92 (1H, s), 7.58-7.53 (1H, m), 7.56 (1H, d, J = 0.7 Hz), 7.27- 7.17 (3H, m), 7.13 (1H, s), 7.05-7.01 (1H, m), 6.64 (1H, d, J = 2.2 Hz), 3.94 (3H, s). 565 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, d, J = 0.7 Hz), 7.67 (1H, d, J = 0.7 Hz), 7.66- 7.62 (1H, m), 7.44-7.29 (5H, m), 7.17 (1H, dd, J = 9.9, 2.6 Hz), 5.06 (1H, d, J = 5.3 Hz), 4.79 (1H, t, J = 5.6 Hz), 4.33 (1H, dd, J = 13.8, 4.1 Hz), 4.11 (1H, dd, J = 13.7, 7.7 Hz), 3.95-3.87 (1H, m), 3.46- 3.35 (2H, m).

TABLE 1-83 compound No. structural formula NMR 566 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.99 (1H, s), 7.68 (1H, s), 7.66-7.62 (1H, m), 7.45- 7.29 (5H, m), 7.16 (1H, dd, J = 9.9, 2.4 Hz), 5.07 (1H, d, J = 5.5 Hz), 4.79 (1H, t, J = 5.5 Hz), 4.34 (1H, dd, J = 13.7, 4.0 Hz), 4.10 (1H, dt, J = 13.7, 7.9 Hz), 3.95-3.86 (1H, m), 3.47- 3.35 (2H, m). 567

¹H-NMR (DMSO-D₆) δ: 7.63 (2H, d, J = 7.0 Hz), 7.42 (1H, t, J = 7.5 Hz), 7.36- 7.28 (2H, m), 7.26-7.18 (2H, m), 6.90-6.85 (1H, m), 3.79 (1.3H, s), 3.78 (1.7H, s), 2.07 (1.3H, s), 1.97 (1.7H, s), 1.95 (1.7H, s), 1.86 (1.3H, s). 568

¹H-NMR (DMSO-D₆) δ: 8.91 (1H, d, J = 2.0 Hz), 8.44 (1H, s), 8.16-8.13 (1H, m), 8.09 (1H, s), 7.89-7.86 (1H, m), 7.74-7.70 (1H, m), 7.62-7.57 (1H, m), 7.54- 7.49 (2H, m), 4.36 (2H, t, J = 6.7 Hz), 2.84 (2H, t, J = 6.6 Hz). 569

¹H-NMR (DMSO-D₆) δ: 7.95 (1H, s), 7.59 (1H, d, J = 0.7 Hz), 7.58-7.55 (1H, m), 7.28-7.19 (3H, m), 7.19- 7.16 (1H, m), 7.13 (1H, s), 6.78 (1H, d, J = 2.3 Hz), 3.95 (3H, s), 3.78-3.73 (4H, m), 3.21-3.17 (4H, m). 570

¹H-NMR (DMSO-D₆) δ: 8.26 (1H, s), 7.91 (1H, s), 7.82-7.78 (1H, m), 7.75- 7.73 (1H, m), 7.72-7.70 (1H, m), 7.68-7.63 (1H, m), 7.54-7.48 (1H, m), 7.40- 7.34 (1H, m), 7.22 (1H, s), 5.47 (1H, t, J = 5.3 Hz), 4.87 (2H, d, J = 5.3 Hz), 3.89 (3H, s). 571

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, d, J = 3.1 Hz), 7.62- 7.57 (2H, m), 7.33-7.18 (4H, m), 7.17-7.13 (1H, m), 6.84-6.80 (1H, m), 5.00- 4.97 (1H, m), 4.72-4.67 (1H, m), 4.11-4.05 (1H, m), 3.98-3.89 (4H, m), 3.86- 3.77 (1H, m), 3.49-3.42 (2H, m). 572

¹H-NMR (DMSO-D₆) δ: 7.85 (1H, d, J = 7.7 Hz), 7.72 (1H, d, J = 1.5 Hz), 7.71- 7.66 (2H, m), 7.58-7.53 (1H, m), 7.47-7.42 (1H, m), 7.33 (1H, s), 5.54 (1H, t, J = 5.5 Hz), 4.95-4.85 (2H, m), 3.50 (2H, t, J = 6.6 Hz), 3.47-3.38 (2H, m), 1.94-1.80 (4H, m).

TABLE 1-84 compound No. structural formula NMR 573 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, s), 7.61 (1H, d, J = 0.7 Hz), 7.60-7.57 (1H, m), 7.29-7.22 (4H, m), 7.12 (1H, d, J = 1.9 Hz), 6.80 (1H, d, J = 2.3 Hz), 4.12 (2H, t, J = 6.1 Hz), 3.95 (3H, s), 3.07 (2H, t, J = 7.5 Hz), 2.22-2.15 (2H, m). 574 (optically active form)

¹H-NMR (CDCl₃) δ: 7.77 (1H, d, J = 0.7 Hz), 7.76 (1H, d, J = 0.7 Hz), 7.70-7.66 (1H, m), 7.54-7.51 (1H, m), 7.29-7.18 (4H, m), 7.13 (1H, dd, J = 1.5, 0.8 Hz), 2.44 (3H, s), 1.97 (6H, s). 575 (optically active form)

¹H-NMR (DMSO-D₆) δ: 12.53 (1H, br s), 7.85 (1H, d, J = 0.7 Hz), 7.64-7.60 (1H, m), 7.59 (1H, d, J = 0.9 Hz), 7.45-7.42 (1H, m), 7.32-7.20 (3H, m), 7.17 (1H, s), 7.10 (1H, dd, J = 1.7, 0.8 Hz), 4.35 (2H, s), 2.38 (3H, s), 1.17 (6H, s). 576 (optically active form)

¹H-NMR (DMSO-D₆) δ: 12.16 (1H, br s), 8.04 (1H, d, J = 0.7 Hz), 7.63-7.57 (1H, m), 7.58 (1H, d, J = 0.7 Hz), 7.43-7.40 (1H, m), 7.32-7.26 (3H, m), 7.15 (1H, s), 7.13 (1H, d, J = 0.9 Hz), 2.94 (2H, s), 2.38 (3H, s), 1.70 (3H, s), 1.69 (3H, s). 577 (optically active form)

¹H-NMR (DMSO-D₆) δ: 12.21 (1H, br s), 7.98 (1H, s), 7.62-7.57 (1H, m), 7.61 (1H, d, J = 0.7 Hz), 7.29- 7.21 (4H, m), 7.14-7.12 (1H, m), 6.82 (1H, d, J = 2.6 Hz), 4.07 (2H, t, J = 6.4 Hz), 3.95 (3H, s), 2.60-2.54 (1H, m), 2.11- 2.01 (1H, m), 1.85-1.75 (1H, m), 1.15 (3H, d, J = 6.7 Hz). 578

¹H-NMR (CDCl₃) δ: 8.42 (1H, d, J = 7.5 Hz), 7.78-7.77 (1H, m), 7.76-7.70 (2H, m), 7.69-7.68 (1H, m), 7.67 (1H, d, J = 1.5 Hz), 7.54- 7.48 (1H, m), 7.42-7.36 (1H, m), 3.94 (3H, s), 3.53 (1H, s), 3.09 (1H, br s). 579

¹H-NMR (DMSO-D₆) δ: 8.29 (1H, s), 8.00 (1H, s), 7.94 (1H, d, J = 0.7 Hz), 7.77- 7.74 (1H, m), 7.67-7.61 (2H, m), 7.50 (1H, d, J = 1.8 Hz), 7.34-7.30 (3H, m), 7.25 (1H, s), 3.97 (3H, s), 3.87 (3H, s).

TABLE 1-85 compound No. structural formula NMR 580

¹H-NMR (DMSO-D₆) δ: 8.30 (1H, d, J = 0.7 Hz), 8.01 (1H, d, J = 0.7 Hz), 7.97 (1H, d, J = 0.7 Hz), 7.78- 7.75 (1H, m), 7.67 (1H, d, J = 0.7 Hz), 7.66-7.62 (1H, m), 7.53 (1H, d, J = 1.6 Hz), 7.39-7.27 (3H, m), 7.26 (1H, s), 5.00 (1H, t, J = 5.2 Hz), 4.95 (1H, t, J = 5.3 Hz), 4.28 (2H, t, J = 5.7 Hz), 4.18 (2H, t, J = 5.7 Hz), 3.85 (2H, dt, J = 5.2, 5.7 Hz), 3.79 (2H, dt, J = 5.2, 5.7 Hz). 581 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.99 (1H, s), 7.63 (1H, d, J = 0.7 Hz), 7.61-7.57 (1H, m), 7.30-7.20 (4H, m), 7.13- 7.11 (1H, m), 6.80 (1H, d, J = 2.6 Hz), 4.42 (2H, t, J = 6.6 Hz), 4.10 (2H, q, J = 7.0 Hz), 2.90 (2H, t, J = 6.7 Hz). 582 (optically active form)

¹H-NMR (DMSO-D₆) δ: 12.20 (1H, br s), 8.01 (1H, s), 7.63 (1H, d, J = 0.7 Hz), 7.62-7.56 (1H, m), 7.28- 7.19 (4H, m), 7.14-7.11 (1H, m), 6.83 (1H, d, J = 2.3 Hz), 4.23 (2H, t, J = 6.8 Hz), 4.11 (2H, q, J = 7.0 Hz), 2.27 (2H, t, J = 7.3 Hz), 2.12-2.05 (2H, m), 1.35 (3H, t, J = 7.0 Hz). 583

¹H-NMR (DMSO-D₆) δ: 7.69- 7.66 (1H, m), 7.63-7.60 (1H, m), 7.49-7.45 (1H, m), 7.33-7.29 (1H, m), 7.20 (1H, s), 7.14 (1H, d, J = 2.6 Hz), 7.09-7.07 (1H, m), 5.47 (1H, t, J = 5.4 Hz), 4.88-4.78 (2H, m), 4.15 (2H, t, J = 5.6 Hz), 3.58 (2H, t, J = 5.4 Hz), 3.48 (2H, t, J = 7.2 Hz), 2.23 (2H, t, J = 8.1 Hz), 1.98- 1.88 (2H, m). 854

¹H-NMR (DMSO-D₆) δ: 8.24 (1H, d, J = 0.9 Hz), 7.94 (1H, d, J = 0.7 Hz), 7.81 (1H, d, J = 7.7 Hz), 7.69- 7.64 (2H, m), 7.57-7.55 (1H, m), 7.54-7.49 (1H, m), 7.39-7.35 (1H, m), 7.19 (1H, s), 4.94 (1H, t, J = 5.3 Hz), 4.18 (2H, t, J = 5.6 Hz), 3.78 (2H, dt, J = 5.6, 5.3 Hz), 2.65 (3H, s). 855

¹H-NMR (DMSO-D₆) δ: 8.39 (1H, d, J = 0.7 Hz), 8.08 (1H, d, J = 0.7 Hz), 8.05 (1H, d, J = 1.6 Hz), 7.95- 7.93 (1H, m), 7.78-7.75 (1H, m), 7.68-7.65 (1H, m), 7.47-7.43 (1H, m), 7.42- 7.38 (1H, m), 7.35 (1H, s), 4.96 (1H, t, J = 5.4 Hz), 4.19 (2H, t, J = 5.6 Hz), 3.79 (2H, dt, J = 5.6, 5.4 Hz), 2.77 (3H, s).

TABLE 1-86 compound No. structural formula NMR 586

¹H-NMR (DMSO-D₆) δ: 8.25- 8.23 (1H, m), 7.91-7.78 (3H, m), 7.71-7.65 (2H, m), 7.54-7.49 (1H, m), 7.39- 7.34 (1H, m), 7.21 (1H, s), 5.51-5.47 (1H, m), 5.46- 5.35 (1H, m), 4.94 (1H, t, J = 5.3 Hz), 4.19 (2H, t, J = 5.7 Hz), 3.81-3.75 (2H, m), 1.50-1.43 (3H, m). 587

¹H-NMR (DMSO-D) δ: 8.44 (1H, s), 8.07 (1H, d, J = 0.5 Hz), 8.05 (1H, d, J = 1.6 Hz), 7.95-7.93 (1H, m), 7.78-7.75 (1H, m), 7.68- 7.65 (1H, m), 7.47-7.43 (1H, m), 7.42-7.38 (1H, m), 7.34 (1H, s), 4.18 (2H, q, J = 7.3 Hz), 2.77 (3H, s), 1.43 (3H, t, J = 7.3 Hz). 588 (optically active form)

¹H-NMR (DMSO-D₆) δ: 12.45 (1H, br s), 8.00 (1H, s), 7.64 (1H, d, J = 0.7 Hz), 7.62-7.58 (1H, m), 7.31- 7.20 (4H, m), 7.16-7.14 (1H, m), 6.84 (1H, d, J = 2.6 Hz), 4.43 (2H, t, J = 6.7 Hz), 3.84 (3H, s), 2.91 (2H, t, J = 6.7 Hz). 589 (optically active form)

¹H-NMR (DMSO-D₆) δ: 12.22 (1H, br s), 8.02 (1H, s), 7.64 (1H, s), 7.62-7.57 (1H, m), 7.30-7.18 (4H, m), 7.16-7.13 (1H, m), 6.86 (1H, d, J = 2.1 Hz), 4.24 (2H, t, J = 6.8 Hz), 3.84 (3H, s), 2.28 (2H, t, J = 7.3 Hz), 2.13-2.06 (2H, m). 590

¹H-NMR (DMSO-D₆) δ: 8.26 (1H, d, J = 0.7 Hz), 7.95 (1H, d, J = 0.9 Hz), 7.82- 7.81 (1H, m), 7.79 (1H, d, J = 7.9 Hz), 7.73 (1H, dd, J = 8.0, 1.7 Hz), 7.58-7.52 (2H, m), 7.37-7.33 (1H, m), 7.22 (1H, s), 5.44 (1H, t, J = 5.4 Hz), 4.94 (1H, t, J = 5.4 Hz), 4.91-4.81 (2H, m), 4.18 (2H, t, J = 5.6 Hz), 3.78 (2H, dt, J = 5.6, 5.4 Hz). 591

¹H-NMR (DMSO-D₆) δ: 8.75 (1H, d, J = 7.9 Hz), 8.28 (1H, s), 7.92 (1H, d, J = 0.9 Hz), 7.71-7.69 (1H, m), 7.65 (1H, d, J = 1.5 Hz), 7.64-7.61 (1H, m), 7.48- 7.43 (1H, m), 7.35-7.30 (1H, m), 7.14 (1H, s), 5.40 (1H, s), 3.89 (3H, s), 1.73 (3H, s), 1.63 (3H, s). 592

¹H-NMR (DMSO-D₆) δ: 8.75 (1H, d, J = 7.9 Hz), 8.27 (1H, d, J = 0.7 Hz), 7.94 (1H, d, J = 0.7 Hz), 7.72- 7.70 (1H, m), 7.65 (1H, d, J = 1.6 Hz), 7.65-7.61 (1H, m), 7.48-7.43 (1H, m), 7.35-7.30 (1H, m), 7.14 (1H, s), 5.41 (1H, s), 4.94 (1H, t, J = 5.3 Hz), 4.18 (2H, t, J = 5.6 Hz), 3.79 (2H, q, J = 5.6 Hz), 1.73 (3H, s), 1.64 (3H, s).

TABLE 1-87 compound No. structural formula NMR 593

¹H-NMR (DMSO-D₆) δ: 8.35 (1H, s), 7.94 (1H, s), 7.85-7.82 (1H, m), 7.78 (1H, d, J = 8.1 Hz), 7.73 (1H, dd, J = 8.1, 1.6 Hz), 7.58-7.51 (2H, m), 7.37- 7.33 (1H, m), 7.21 (1H, s), 5.44 (1H, t, J = 5.3 Hz), 4.90-4.81 (2H, m), 4.57- 4.50 (1H, m), 1.47 (3H, s), 1.46 (3H, s). 594

¹H-NMR (DMSO-D₆) δ: 12.42 (1H, br s), 8.42 (1H, d, J = 0.7 Hz), 8.08 (1H, d, J = 0.9 Hz), 8.04 (1H, d, J = 1.5 Hz), 7.94-7.92 (1H, m), 7.78-7.75 (1H, m), 7.68- 7.65 (1H, m), 7.47-7.43 (1H, m), 7.42-7.38 (1H, m), 7.35 (1H, s), 4.36 (2H, t, J = 6.7 Hz), 3.38 (3H, t, J = 6.9 Hz), 2.87 (2H, t, J = 6.7 Hz), 2.77 (3H, s). 595 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.02 (1H, d, J = 0.5 Hz), 7.68 (1H, d, J = 0.5 Hz), 7.65- 7.61 (1H, m), 7.44-7.37 (2H, m), 7.40 (1H, s), 7.36-7.25 (2H, m), 7.18 (1H, dd, J = 10.0, 2.6 Hz), 4.97 (2H, t, J = 5.3 Hz), 4.39-4.32 (1H, m), 3.86- 3.76 (4H, m). 596

¹H-NMR (DMSO-D₆) δ: 8.38 (1H, s), 8.06 (1H, d, J = 0.5 Hz), 8.04 (1H, d, J = 1.6 Hz), 7.94-7.91 (1H, m), 7.76 (1H, d, J = 7.4 Hz), 7.68-7.64 (1H, m), 7.48- 7.43 (1H, m), 7.42-7.38 (1H, m), 7.35 (1H, s), 3.90 (3H, s), 2.77 (3H, s). 597

¹H-NMR (DMSO-D₆) δ: 8.32 (1H, d, J = 0.5 Hz), 7.94 (1H, d, J = 0.7 Hz), 7.82 (1H, br s), 7.79 (1H, d, J = 8.1 Hz), 7.72 (1H, dd, J = 8.1, .16 Hz), 7.58-7.52 (2H, m), 7.37-7.33 (1H, m), 7.22 (1H, s), 5.44 (1H, t, J = 5.4 Hz), 4.90-4.81 (2H, m), 4.17 (2H, q, J = 7.3 Hz), 1.42 (3H, t, J = 7.3 Hz). 598

¹H-NMR (DMSO-D₆) δ: 8.26 (1H, d, J = 4.4 Hz), 7.90- 7.79 (3H, m), 7.69-7.65 (2H, m), 7.54-7.49 (1H, m), 7.39-7.34 (1H, m), 7.21 (1H, s), 5.48 (1H, br s), 5.44 (0.5H, q, J = 6.3 Hz), 5.38 (0.5H, q, J = 6.4 Hz), 3.89 (3H, s), 1.48 (1.6H, d, J = 6.3 Hz), 1.45 (1.4H, d, J = 6.3 Hz). 599

¹H-NMR (CDCl₃) δ: 7.82-7.80 (1H, m), 7.71-7.66 (1H, m), 7.43-7.35 (2H, m), 7.35- 7.29 (1H, m), 7.11 (1H, d, J = 2.3 Hz), 4.16 (2H, t, J = 5.3 Hz), 3.70 (1H, br s), 3.64 (2H, t, J = 5.2 Hz), 3.57 (2H, t, J = 7.0 Hz), 2.68 (3H, s), 2.34 (2H, t, J = 8.0 Hz), 2.08-1.98 (2H, m).

TABLE 1-88 compound No. structural formula NMR 600

¹H-NMR (DMSO-D₆) δ: 8.29 (1H, s), 7.96 (1H, s), 7.82-7.77 (2H, m), 7.72 (1H, dd, J = 8.0, 1.7 Hz), 7.58-7.52 (2H, m), 7.37- 7.33 (1H, m), 4.88 (1H, d, J = 13.7 Hz), 4.84 (1H, d, J = 13.7 Hz), 4.36 (2H, t, J = 6.7 Hz), 2.86 (2H, t, J = 6.7 Hz). 601

¹H-NMR (DMSO-D₆) δ: 8.23 (1H, d, J = 0.5 Hz), 7.95 (1H, d, J = 0.7 Hz), 7.80- 7.77 (2H, m), 7.71 (1H, dd, J = 8.0, 1.7 Hz), 7.57-7.52 (2H, m), 7.42 (1H, br s), 7.37-7.33 (1H, m), 7.23 (1H, s), 6.92 (1H, br s), 5.44 (1H, t, J = 5.4 Hz), 4.90-4.81 (2H, m), 4.34 (2H, t, J = 6.8 Hz), 2.67 (2H, t, J = 7.0 Hz). 602

¹H-NMR (DMSO-D₆) δ: 8.39 (1H, s), 7.95 (1H, s), 7.88-7.86 (1H, m), 7.79- 7.74 (2H, m), 7.58-7.52 (2H, m), 7.37-7.33 (1H, m), 7.20 (1H, s), 5.44 (1H, t, J = 5.4 Hz), 4.90-4.81 (2H, m), 1.58 (9H, s). 603

¹H-NMR (DMSO-D₆) δ: 8.39- 8.36 (1H, m), 8.34 (1H, d, J = 0.4 Hz), 7.99 (1H, d, J = 0.9 Hz), 7.81-7.79 (1H, m), 7.75 (1H, d, J = 1.5 Hz), 7.69-7.66 (1H, m), 7.56-7.52 (1H, m), 7.45- 7.41 (1H, m), 7.35 (1H, s), 5.56 (1H, t, J = 6.0 Hz), 4.50 (2H, d, J = 6.0 Hz), 3.87 (3H, s). 604 (optically active form)

¹H-NMR (DMSO-D₆) δ: 9.37 (1H, s), 8.96 (2H, br s), 7.63 (1H, d, J = 7.3 Hz), 7.38 (1H, br s), 7.31-7.21 (3H, m), 7.04 (1H, d, J = 2.4 Hz), 6.63-6.59 (1H, m), 4.11 (2H, t, J = 6.5 Hz), 2.41 (2H, t, J = 7.3 Hz), 2.01-1.94 (2H, m). 605 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.93 (1H, d, J = 0.7 Hz), 7.63- 7.59 (1H, m), 7.61 (1H, d, J = 0.7 Hz), 7.42 (1H, s), 7.37 (1H, dd, J = 6.7, 0.9 Hz), 7.32-7.22 (2H, m), 7.16 (1H, s), 7.14 (1H, dd, J = 1.6, 0.7 Hz), 4.96 (2H, td, J = 5.3, 1.2 Hz), 4.38- 4.32 (1H, m), 3.86-3.76 (4H, m), 2.39 (3H, s). 606 (optically active form)

¹H-NMR (DMSO-D₆) δ: 12.07 (1H, br s), 7.99 (1H, d, J = 0.7 Hz), 7.64-7.60 (1H, m), 7.59 (1H, d, J = 0.7 Hz), 7.42 (1H, s), 7.32- 7.21 (3H, m), 7.17 (1H, s), 7.12 (1H, dd, J = 1.5, 0.8 Hz), 4.21 (2H, t, J = 6.7 Hz), 2.38 (3H, s), 2.28 (2H, t, J = 7.4 Hz), 1.91- 1.84 (2H, m), 1.55-1.48 (2H, m).

TABLE 1-89 compound No. structural formula NMR 607 (optically active form)

¹H-NMR (DMSO-D₆) δ: 12.53 (1H, br s), 7.94 (1H, d, J = 0.7 Hz), 7.67 (1H, d, J = 0.7 Hz), 7.65 (1H, d, J = 7.0 Hz), 7.43-7.39 (2H, m), 7.37-7.24 (3H, m), 7.17 (1H, dd, J = 10.0, 2.6 Hz), 4.36 (2H, s), 1.18 (6H, s). 608

¹H-NMR (DMSO-D₆) δ: 13.15 (1H, br s), 8.29 (1H, s), 7.99 (1H, d, J = 0.5 Hz), 7.83-7.79 (2H, m), 7.74 (1H, dd, J = 8.1, 1.6 Hz), 7.58-7.52 (2H, m), 7.38- 7.33 (1H, m), 7.24 (1H, s), 5.45 (1H, t, J = 5.3 Hz), 5.00 (2H, s), 4.91-4.82 (2H, m). 609

¹H-NMR (DMSO-D₆) δ: 8.27- 8.25 (1H, m), 7.98-7.96 (1H, m), 7.84-7.79 (2H, m), 7.76-7.72 (1H, m), 7.58- 7.51 (3H, m), 7.38-7.33 (1H, m), 7.31 (1H, br s), 7.24 (1H, d, J = 1.9 Hz), 5.47-5.43 (1H, m), 4.87- 4.86 (2H, m), 4.80 (2H, d, J = 1.6 Hz). 610 (optically active form)

¹H-NMR (DMSO-D₆) δ: 12.19 (1H, br s), 8.14 (1H, d, J = 0.7 Hz), 7.66 (1H, s), 7.65-7.61 (1H, m), 7.41- 7.37 (2H, m), 7.37-7.29 (3H, m), 7.18 (1H, dd, J = 10.0, 2.6 Hz), 2.94 (2H, s), 1.70 (3H, s), 1.69 (3H, s). 611

¹H-NMR (DMSO-D₆) δ: 7.67 (1H, d, J = 7.7 Hz), 7.61 (1H, d, J = 7.4 Hz), 7.49- 7.44 (1H, m), 7.32-7.28 (1H, m), 7.19 (1H, s), 7.13 (1H, d, J = 2.3 Hz), 7.07- 7.05 (1H, m), 5.46 (1H, t, J = 5.4 Hz), 4.87-4.78 (2H, m), 4.47 (1H, t, J = 5.2 Hz), 4.05 (2H, t, J = 6.5 Hz), 3.47 (2H, dd, J = 11.6, 6.5 Hz), 1.82-1.75 (2H, m), 1.63-1.55 (2H, m). 612

¹H-NMR (DMSO-D₆) δ: 8.09 (1H, br s), 7.86 (1H, d, J = 7.6 Hz), 7.72 (1H, br s), 7.61 (1H, d, J = 7.4 Hz), 7.46-7.41 (1H, m), 7.35- 7.29 (1H, m), 7.30 (1H, s), 7.25-7.23 (1H, m), 7.07 (1H, d, J = 2.5 Hz), 4.23 (2H, t, J = 5.7 Hz), 4.20- 4.16 (2H, m), 3.67-3.59 (2H, m), 3.46 (2H, t, J = 6.4 Hz), 1.98-1.92 (2H, m). 613

¹H-NMR (DMSO-D₆) δ: 12.16 (1H, br s), 8.64 (1H, s), 7.64 (1H, d, J = 7.4 Hz), 7.59 (1H, s), 7.40-7.31 (3H, m), 7.30-7.28 (1H, m), 7.13 (1H, d, J = 2.6 Hz), 7.06 (1H, d, J = 7.0 Hz), 4.11 (2H, t, J = 6.5 Hz), 2.42 (2H, t, J = 7.3 Hz), 2.01-1.94 (2H, m).

TABLE 1-90 compound No. structural formula NMR 614 (optically active form)

¹H-NMR (CDCl₃) δ: 7.71 (2H, s), 7.68-7.64 (1H, m), 7.25-7.22 (3H, m), 7.11- 7.08 (1H, m), 6.80-6.79 (1H, m), 3.88 (3H, s), 3.15 (2H, s), 2.79 (1H, s), 1.78 (3H, s), 1.77 (3H, s). 615

¹H-NMR (DMSO-D₆) δ: 8.25 (1H, s), 7.93 (1H, s), 7.80 (1H, d, J = 7.7 Hz), 7.76- 7.74 (1H, m), 7.73-7.71 (1H, m), 7.67-7.64 (1H, m), 7.53-7.49 (1H, m), 7.39- 7.34 (1H, m), 7.23 (1H, s), 5.47 (1H, t, J = 5.3 Hz), 4.95 (1H, t, J = 5.3 Hz), 4.91-4.83 (2H, m), 4.19 (2H, t, J = 5.6 Hz), 3.78 (2H, q, J = 5.5 Hz). 616

¹H-NMR (CDCl₃) δ: 8.28-8.25 (1H, m), 7.88 (1H, d, J = 2.0 Hz), 7.84-7.82 (1H, m), 7.73-7.69 (1H, m), 7.51- 7.46 (1H, m), 7.44-7.40 (1H, m), 4.01 (3H, s), 2.83 (1H, br s). 617 (optically active form)

¹H-NMR (CDCl₃) δ: 8.30-8.27 (1H, m), 7.89 (1H, d, J = 2.0 Hz), 7.84-7.82 (1H, m), 7.73-7.70 (1H, m), 7.52- 7.47 (1H, m), 7.44-7.40 (1H, m), 4.02 (3H, s), 2.77 (1H, br s). 618

¹H-NMR (DMSO-D₆) δ: 8.31 (1H, d, J = 0.7 Hz), 7.92 (1H, d, J = 0.7 Hz), 7.80 (1H, d, J = 7.7 Hz), 7.75 (1H, d, J = 1.4 Hz), 7.73- 7.71 (1H, m), 7.67-7.64 (1H, m), 7.53-7.48 (1H, m), 7.39-7.34 (1H, m), 7.22 (1H, s), 5.47 (1H, t, J = 5.4 Hz), 4.91-4.82 (2H, m), 4.18 (2H, q, J = 7.3 Hz), 1.42 (3H, t, J = 7.3 Hz). 619 (optically active form)

¹H-NMR (DMSO-D₆) δ: 12.55 (1H, br s), 7.89 (1H, d, J = 0.7 Hz), 7.63 (1H, d, J = 0.7 Hz), 7.62-7.59 (1H, m), 7.28-7.24 (3H, m), 7.21- 7.15 (2H, m), 6.83 (1H, d, J = 2.3 Hz), 4.36 (2H, s), 3.84 (3H, s), 1.19 (6H, s). 620

¹H-NMR (DMSO-D₆) δ: 7.94 (1H, d, J = 0.7 Hz), 7.64- 7.58 (2H, m), 7.60 (1H, d, J = 0.7 Hz), 7.38-7.26 (3H, m), 7.24-7.21 (1H, m), 7.19 (1H, br s), 5.35 (1H, t, J = 5.6 Hz), 4.97 (1H, t, J = 5.2 Hz), 4.57 (2H, d, J = 5.3 Hz), 4.26 (2H, t, J = 5.6 Hz), 3.82 (2H, dt, J = 5.6, 5.6 Hz).

TABLE 1-91 compound No. structural formula NMR 621

¹H-NMR (DMSO-D₆) δ: 8.34 (1H, s), 7.91 (1H, s), 7.80 (1H, d, J = 7.7 Hz), 7.76- 7.75 (1H, m), 7.75-7.73 (1H, m), 7.68-7.64 (1H, m), 7.53-7.48 (1H, m), 7.39- 7.34 (1H, m), 7.21 (1H, s), 5.46 (1H, t, J = 5.4 Hz), 4.91-4.82 (2H, m), 4.59- 4.49 (1H, m), 1.48 (3H, s), 1.46 (3H, s). 622

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, s), 7.62-7.57 (1H, m), 7.61 (1H, d, J = 0.7 Hz), 7.31-7.22 (4H, m), 7.17- 7.13 (1H, m), 6.82 (1H, d, J = 2.6 Hz), 4.56 (2H, t, J = 5.2 Hz), 4.04 (2H, d, J = 6.0 Hz), 3.95 (3H, s), 3.58-3.48 (4H, m), 2.04- 1.95 (1H, m). 623

¹H-NMR (DMSO-D₆) δ: 12.20 (1H, br s), 7.98 (1H, d, J = 0.5 Hz), 7.65-7.58 (2H, m), 7.61 (1H, d, J = 0.7 Hz), 7.34-7.20 (5H, m), 5.35 (1H, t, J = 5.7 Hz), 4.57 (2H, d, J = 5.3 Hz), 4.24 (2H, t, J = 6.8 Hz), 2.27 (2H, t, J = 7.4 Hz), 2.12-2.05 (2H, m). 624 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, d, J = 0.7 Hz), 7.63 (1H, d, J = 0.7 Hz), 7.61- 7.56 (1H, m), 7.34-7.29 (1H, m), 7.28-7.23 (2H, m), 7.21 (1H, s), 7.14-7.11 (1H, m), 6.82 (1H, d, J = 2.3 Hz), 4.97 (1H, t, J = 5.2 Hz), 4.46 (1H, t, J = 5.2 Hz), 4.25 (2H, t, J = 5.7 Hz), 4.05 (2H, t, J = 6.5 Hz), 3.85-3.79 (2H, m), 3.49-3.43 (2H, m), 1.81- 1.74 (2H, m), 1.61-1.54 (2H, m). 625

¹H-NMR (DMSO-D₆) δ: 7.89 (1H, d, J = 7.7 Hz), 7.74- 7.70 (1H, m), 7.66-7.58 (3H, m), 7.52 (1H, s), 7.52-7.47 (1H, m), 4.54 (1H, d, J = 18.8 Hz), 4.49 (1H, d, J = 18.8 Hz). 626

¹H-NMR (DMSO-D₆) δ: 8.10 (1H, br s), 7.85 (1H, d, J = 7.7 Hz), 7.72 (1H, br s), 7.63-7.59 (1H, m), 7.45- 7.40 (1H, m), 7.34-7.29 (1H, m), 7.30 (1H, s), 7.23-7.21 (1H, m), 7.04 (1H, d, J = 2.6 Hz), 3.86 (3H, s).

TABLE 1-92 compound No. structural formula NMR 627

¹H-NMR (DMSO-D₆) δ: 7.67 (1H, d, J = 7.9 Hz), 7.63- 7.60 (1H, m), 7.49-7.44 (1H, m), 7.33-7.28 (1H, m), 7.20 (1H, s), 7.14 (1H, d, J = 2.3 Hz), 7.09-7.07 (1H, m), 5.48 (1H, t, J = 5.4 Hz), 4.88-4.78 (2H, m), 3.83 (3H, s). 628

¹H-NMR (DMSO-D₆) δ: 7.96 (1H, s), 7.61-7.57 (1H, m), 7.59 (1H, d, J = 0.7 Hz), 7.30-7.18 (5H, m), 6.87 (1H, d, J = 2.4 Hz), 4.87- 4.82 (2H, m), 4.35-4.29 (1H, m), 3.95 (3H, s), 3.66-3.54 (4H, m). 629 (optically active form)

¹H-NMR (DMSO-D6) δ: 8.31 (1H, d, J = 0.7 Hz), 7.91 (1H, d, J = 0.9 Hz), 7.80 (1H, d, J = 7.7 Hz), 7.75 (1H, d, J = 1.5 Hz), 7.73- 7.71 (1H, m), 7.67-7.64 (1H, m), 7.53-7.48 (1H, m), 7.39-7.34 (1H, m), 7.21 (1H, s), 5.46 (1H, t, J = 5.4 Hz), 4.92-4.82 (2H, m), 4.18 (2H, q, J = 7.3 Hz), 1.42 (3H, t, J = 7.3 Hz). 630 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.37 (1H, s), 8.14 (1H, br s), 7.98 (1H, d, J = 0.7 Hz), 7.91 (1H, d, J = 7.7 Hz), 7.85-7.83 (1H, m), 7.74 (1H, br s), 7.70 (1H, d, J = 1.5 Hz), 7.67-7.63 (1H, m), 7.49-7.44 (1H, m), 7.40-7.35 (1H, m), 7.30 (1H, s), 4.17 (2H, q, J = 7.3 Hz), 1.42 (3H, t, J = 7.3 Hz). 631

¹H-NMR (DMSO-D₆) δ: 7.96 (1H, d, J = 0.9 Hz), 7.65- 7.60 (1H, m), 7.62 (1H, d, J = 0.9 Hz), 7.42-7.35 (2H, m), 7.33-7.27 (2H, m), 7.17 (1H, s), 7.09 (1H, d, J = 1.6 Hz), 4.98 (1H, t, J = 5.2 Hz), 4.26 (2H, t, J = 5.7 Hz), 3.83 (2H, q, J = 5.5 Hz), 2.60-2.47 (2H, m), 1.92-1.82 (1H, m), 0.93 (3H, d, J = 6.7 Hz), 0.91 (3H, d, J = 6.5 Hz). 632

¹H-NMR (DMSO-D₆) δ: 8.22 (1H, br s), 7.95-7.92 (1H, m), 7.81 (1H, br s), 7.73- 7.66 (2H, m), 7.58 (1H, d, J = 1.4 Hz), 7.53-7.48 (1H, m), 7.47-7.42 (1H, m), 7.44 (1H, s), 4.41 (1H, s). 633

¹H-NMR (DMSO-D₆) δ: 8.09 (1H, br s), 7.90 (1H, d, J = 7.7 Hz), 7.68 (1H, br s), 7.65-7.62 (1H, m), 7.55- 7.53 (1H, m), 7.47-7.43 (1H, m), 7.39-7.34 (1H, m), 7.33 (1H, d, J = 1.6 Hz), 7.25 (1H, s), 2.71 (2H, q, J = 7.6 Hz), 1.23 (3H, t, J = 7.5 Hz).

TABLE 1-93 compound No. structural formula NMR 634

¹H-NMR (DMSO-D₆) δ: 8.06 (1H, br s), 7.91 (1H, d, J = 7.7 Hz), 7.67 (1H, br s), 7.65-7.61 (1H, m), 7.55- 7.52 (1H, m), 7.47-7.42 (1H, m), 7.38-7.32 (2H, m), 7.23 (1H, s), 2.71-2.63 (2H, m), 0.95 (9H, t, J = 7.9 Hz), 0.92-0.86 (2H, m), 0.56 (6H, q, J = 7.9 Hz). 635

¹H-NMR (DMSO-D₆) δ: 7.78 (1H, d, J = 7.7 Hz), 7.70- 7.66 (1H, m), 7.64-7.61 (1H, m), 7.57-7.52 (2H, m), 7.46-7.40 (1H, m), 7.41 (1H, s), 5.62 (1H, t, J = 5.6 Hz), 4.93-4.82 (2H, m). 636

¹H-NMR (DMSO-D₆) δ: 8.24 (1H, br s), 7.92-7.89 (1H, m), 7.86 (1H, br s), 7.69- 7.64 (2H, m), 7.56 (1H, d, J = 2.1 Hz), 7.53-7.47 (1H, m), 7.49 (1H, s), 7.46-7.41 (1H, m). 637

¹H-NMR (DMSO-D₆) δ: 8.22 (1H, s), 7.89 (1H, d, J = 0.8 Hz), 7.84 (1H, d, J = 7.7 Hz), 7.69-7.68 (1H, m), 7.67-7.63 (1H, m), 7.58 (1H, d, J = 1.6 Hz), 7.55 (1H, br s), 7.51-7.46 (1H, m), 7.38-7.34 (1H, m), 7.22 (1H, s), 7.09 (1H, br s), 3.89 (3H, s), 3.89 (1H, d, J = 15.7 Hz), 3.81 (1H, d, J = 15.7 Hz). 638

¹H-NMR (DMSO-D₆) δ: 8.38 (1H, s), 7.93 (1H, s), 7.81 (1H, d, J = 7.7 Hz), 7.78 (2H, s), 7.66 (1H, d, J = 7.4 Hz), 7.53-7.48 (1H, m), 7.39-7.34 (1H, m), 7.20 (1H, s), 5.45 (1H, t, J = 5.4 Hz), 4.92-4.82 (2H, m), 1.58 (9H, s). 639

¹H-NMR (DMSO-D₆) δ: 8.46 (1H, s), 8.13 (1H, br s), 7.99 (1H, s), 7.91 (1H, d, J = 7.7 Hz), 7.89 (1H, br s), 7.78-7.73 (2H, m), 7.67-7.63 (1H, m), 7.49- 7.44 (1H, m), 7.40-7.34 (1H, m), 7.30 (1H, s), 1.57 (9H, s). 640

¹H-NMR (DMSO-D₆) δ: 8.09 (1H, br s), 7.85 (1H, d, J = 7.7 Hz), 7.71 (1H, br s), 7.63-7.59 (1H, m), 7.45- 7.40 (1H, m), 7.34-7.28 (1H, m), 7.30 (1H, s), 7.24-7.21 (1H, m), 7.04 (1H, d, J = 2.3 Hz), 4.93 (1H, t, J = 5.6 Hz), 4.09 (2H, t, J = 4.9 Hz), 3.74 (2H, q, J = 5.0 Hz).

TABLE 1-94 compound No. structural formula NMR 641

¹H-NMR (DMSO-D₆) δ: 7.84- 7.81 (1H, m), 7.71-7.65 (2H, m), 7.60-7.58 (1H, m), 7.57-7.52 (1H, m), 7.46- 7.41 (1H, m), 7.33 (1H, s), 5.53 (1H, t, J = 5.5 Hz), 4.91-4.81 (2H, m), 4.31 (1H, s). 642

¹H-NMR (DMSO-D₆) δ: 7.79- 7.75 (1H, m), 7.66-7.62 (1H, m), 7.52-7.46 (1H, m), 7.42-7.38 (2H, m), 7.37- 7.33 (1H, m), 7.13 (1H, s), 5.40 (1H, t, J = 5.4 Hz), 4.88-4.78 (2H, m), 2.69 (2H, q, J = 7.6 Hz), 1.23 (3H, t, J = 7.5 Hz). 643

¹H-NMR (DMSO-D₆) δ: 8.24 (1H, s), 7.91 (1H, d, J = 0.7 Hz), 7.83 (1H, d, J = 7.7 Hz), 7.68-7.64 (2H, m), 7.56-7.50 (2H, m), 7.40- 7.35 (1H, m), 7.19 (1H, s), 4.91 (1H, t, J = 5.3 Hz), 3.88 (3H, s), 3.74-3.67 (2H, m), 3.24-3.09 (2H, m). 644

¹H-NMR (DMSO-D₆) δ: 7.86 (1H, d, J = 7.7 Hz), 7.83- 7.81 (1H, m), 7.79-7.77 (1H, m), 7.70 (1H, d, J = 7.5 Hz), 7.58-7.54 (1H, m), 7.48-7.43 (1H, m), 7.35 (1H, s), 5.76 (1H, d, J = 6.2 Hz), 5.56 (1H, t, J = 5.5 Hz), 4.96-4.86 (2H, m), 4.56-4.43 (2H, m), 4.34- 4.24 (1H, m), 4.11-4.00 (1H, m), 3.88-3.76 (1H, m). 645

¹H-NMR (DMSO-D₆) δ: 8.36 (1H, d, J = 0.7 Hz), 8.15 (1H, br s), 8.00 (1H, d, J = 0.7 Hz), 7.91 (1H, d, J = 7.7 Hz), 7.86-7.83 (1H, m), 7.75 (1H, br s), 7.70 (1H, d, J = 1.6 Hz), 7.67-7.63 (1H, m), 7.49-7.44 (1H, m), 7.40-7.35 (1H, m), 7.31 (1H, s), 3.95 (2H, d, J = 7.2 Hz), 2.20-2.13 (1H, m), 0.88 (3H, d, J = 1.2 Hz), 0.86 (3H, d, J = 1.4 Hz). 646

¹H-NMR (DMSO-D₆) δ: 8.32 (1H, s), 8.15 (1H, br s), 8.00 (1H, s), 7.91 (1H, d, J = 7.7 Hz), 7.86-7.84 (1H, m), 7.75 (1H, br s), 7.71 (1H, d, J = 1.6 Hz), 7.67- 7.63 (1H, m), 7.49-7.44 (1H, m), 7.40-7.35 (1H, m), 7.31 (1H, s), 3.95 (2H, s), 0.94 (9H, s). 647 (optically active form)

¹H-NMR (CDCl₃) δ: 8.41-8.37 (1H, m), 8.24-8.22 (1H, m), 8.11 (1H, d, J = 1.5 Hz), 7.79-7.75 (1H, m), 7.59- 7.54 (1H, m), 7.51-7.46 (1H, m), 3.92 (3H, s), 3.06 (1H, br s).

TABLE 1-95 compound No. structural formula NMR 648

¹H-NMR (DMSO-D₆) δ: 7.94 (1H, s), 7.63-7.59 (1H, m), 7.61 (1H, d, J = 0.7 Hz), 7.40-7.37 (2H, m), 7.32- 7.22 (2H, m), 7.15 (1H, s), 7.10 (1H, d, J = 1.5 Hz), 4.96-4.92 (2H, m), 4.38- 4.32 (1H, m), 3.85-3.78 (4H, m), 2.58-2.48 (2H, m), 1.92-1.82 (1H, m), 0.92 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6.6 Hz). 649

¹H-NMR (DMSO-D₆) δ: 8.28 (1H, d, J = 0.7 Hz), 7.93 (1H, d, J = 0.7 Hz), 7.80 (1H, d, J = 7.9 Hz), 7.76- 7.74 (1H, m), 7.73-7.71 (1H, m), 7.66 (1H, d, J = 7.3 Hz), 7.53-7.48 (1H, m), 7.39-7.35 (1H, m), 4.89 (1H, d, J = 13.5 Hz), 4.85 (1H, d, J = 13.7 Hz), 3.96 (2H, d, J = 7.1 Hz), 2.21- 2.13 (1H, m), 0.88 (3H, d, J = 1.1 Hz), 0.86 (3H, d, J = 1.1 Hz). 650

¹H-NMR (DMSO-D₆) δ: 8.24 (1H, d, J = 0.7 Hz), 7.93 (1H, d, J = 0.7 Hz), 7.80 (1H, d, J = 7.7 Hz), 7.76 (1H, d, J = 1.8 Hz), 7.73 (1H, s), 7.66 (1H, d, J = 7.5 Hz), 7.53-7.49 (1H, m), 7.39-7.34 (1H, m), 4.89 (1H, d, J = 13.7 Hz), 4.85 (1H, d, J = 14.1 Hz), 3.95 (3H, s), 0.94 (8H, s). 651

¹H-NMR (DMSO-D₆) δ: 7.96 (1H, s), 7.64-7.59 (2H, m), 7.63 (1H, s), 7.39-7.35 (1H, m), 7.33-7.23 (3H, m), 7.21 (1H, s), 6.55-6.48 (1H, m), 6.40 (1H, dq, J = 17.2, 5.3 Hz), 4.98-4.93 (2H, m), 4.38-4.32 (1H, m), 3.86-3.77 (4H, m), 1.88 (3H, dd, J = 6.5, 1.2 Hz). 652

¹H-NMR (DMSO-D₆) δ: 7.93 (1H, d, J = 0.7 Hz), 7.63- 7.59 (2H, m), 7.61 (1H, d, J = 0.7 Hz), 7.44-7.41 (1H, m), 7.39-7.36 (1H, m), 7.32-7.22 (2H, m), 7.15 (1H, s), 7.13 (1H, d, J = 1.5 Hz), 4.96-4.93 (2H, m), 4.38-4.32 (1H, m), 3.86- 3.78 (4H, m), 3.69-2.60 (2H, m), 1.70-1.57 (2H, m), 0.93 (3H, t, J = 7.4 Hz). 653

¹H-NMR (DMSO-D₆) δ: 7.94 (1H, s), 7.64-7.59 (1H, m), 7.61 (1H, s), 7.47-7.44 (1H, m), 7.39-7.35 (1H, m), 7.32-7.22 (2H, m), 7.17 (1H, s), 7.15 (1H, d, J = 1.2 Hz), 4.98-4.93 (2H, m), 4.38-4.32 (1H, m), 3.86- 3.78 (4H, m), 2.69 (2H, q, J = 7.5 Hz), 1.23 (3H, t, J = 7.7 Hz).

TABLE 1-96 compound No. structural formula NMR 654

¹H-NMR (DMSO-D₆) δ: 7.93 (1H, d, J = 0,7 Hz), 7.61 (1H, d, J = 0.7 Hz), 7.60- 7.58 (1H, m), 7.49-7.46 (1H, m), 7.38-7.33 (1H, m), 7.31-7.21 (2H, m), 7.16 (2H, br s), 4.98-4.93 (2H, m), 4.37-4.31 (1H, m), 3.85-3.76 (4H, m), 3.02- 2.94 (1H, m), 1.26 (3H, d, J = 7.2 Hz), 1.25 (3H, d, J = 7.2 Hz). 655

¹H-NMR (DMSO-D₆) δ: 8.06 (1H, br s), 7.92 (1H, d, J = 7.7 Hz), 7.69 (1H, br s), 7.63 (1H, d, J = 7.2 Hz), 7.55 (1H, br s), 7.47-7.42 (1H, m), 7.38-7.34 (1H, m), 7.34 (1H, d, J = 1.6 Hz), 7.25 (1H, s), 3.34 (2H, t, J = 6.8 Hz), 3.28-3.20 (2H, m), 2.68-2.60 (2H, m), 2.23-2.17 (2H, m), 1.94- 1.85 (2H, m), 1.85-1.75 (2H, m). 656

¹H-NMR (DMSO-D₆) δ: 7.77 (1H, d, J = 7.7 Hz), 7.64 (1H, d, J = 7.4 Hz), 7.52- 7.47 (1H, m), 7.41 (1H, br s), 7.40 (1H, br s), 7.38- 7.33 (1H, m), 7.15 (1H, s), 5.41 (1H, t, J = 5.3 Hz), 4.87-4.78 (2H, m), 3.34 (2H, t, J = 6.7 Hz), 3.24 (2H, t, J = 7.2 Hz), 2.65- 2.61 (2H, m), 2.23-2.18 (2H, m), 1.94-1.86 (2H, m), 1.83-1.74 (2H, m). 657 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.02 (1H, d, J = 0.7 Hz), 7.71- 7.65 (2H, m), 7.67 (1H, d, J = 0.7 Hz), 7.48-7.31 (4H, m), 7.34 (1H, s), 4.97 (1H, t, J = 5.3 Hz), 4.26 (2H, t, J = 5.6 Hz), 3.83 (2H, dt, J = 5.3, 5.6 Hz), 3.52- 3.42 (4H, m), 1.93-1.80 (4H, m). 658

¹H-NMR (DMSO-D₆) δ: 9.24 (1H, s), 9.23 (2H, br s), 8.23 (1H, br s), 8.09 (1H, br s), 8.03 (1H, d, J = 7.7 Hz), 7.97 (1H, d, J = 1.9 Hz), 7.86 (1H, br s), 7.71 (1H, d, J = 7.4 Hz), 7.55- 7.50 (1H, m), 7.48-7.43 (1H, m), 7.45 (1H, s). 659 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.31 (1H, s), 8.14 (1H, br s), 7.99 (1H, d, J = 0.5 Hz), 7.91 (1H, d, J = 7.4 Hz), 7.84 (1H, br s), 7.74 (1H, br s), 7.71 (1H, d, J = 1.6 Hz), 7.64 (1H, d, J = 7.4 Hz), 7.48-7.43 (1H, m), 7.40-7.34 (1H, m), 7.31 (1H, s), 3.94 (2H, s), 0.93 (9H, s).

TABLE 1-97 compound No. structural formula NMR 660 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.25 (1H, d, J = 0.7 Hz), 7.93 (1H, d, J = 0.7 Hz), 7.80 (1H, d, J = 7.9 Hz), 7.76 (1H, d, J = 1.6 Hz), 7.74- 7.72 (1H, m), 7.66 (1H, d, J = 7.4 Hz), 7.54-7.48 (1H, m), 7.40-7.34 (1H, m), 7.22 (1H, s), 5.46 (1H, br s), 4.92-4.83 (2H, m), 3.95 (2H, s), 0.94 (9H, s). 661

¹H-NMR (DMSO-D₆) δ: 8.18 (1H, s), 7.93 (1H, d, J = 0.7 Hz), 7.80 (1H, d, J = 7.7 Hz), 7.75 (1H, d, J = 1.4 Hz), 7.73-7.71 (1H, m), 7.66 (1H, d, J = 7.7 Hz), 7.54-7.48 (1H, m), 7.39- 7.34 (1H, m), 7.23 (1H, s), 5.47 (1H, t, J = 5.4 Hz), 4.92-4.83 (2H, m), 4.76 (1H, s), 4.06 (2H, s), 1.10 (3H, s), 1.10 (3H, s). 662

¹H-NMR (DMSO-D₆) δ: 8.33 (1H, s), 8.13 (1H, br s), 7.98 (1H, s), 7.92 (1H, d, J = 7.7 Hz), 7.84 (1H, br s), 7.73 (1H, br s), 7.70 (1H, d, J = 1.8 Hz), 7.65 (1H, d, J = 7.5 Hz), 7.49- 7.44 (1H, m), 7.40-7.35 (1H, m), 7.30 (1H, s), 3.98 (2H, d, J = 7.1 Hz), 1.92- 1.80 (1H, m), 1.72-1.50 (5H, m), 1.26-1.10 (3H, m), 1.03-0.92 (2H, m). 663 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.92 (1H, s), 7.63-7.59 (1H, m), 7.60 (1H, d, J = 0.7 Hz), 7.44-7.41 (1H, m), 7.33- 7.25 (3H, m), 7.16 (1H, s), 7.13-7.11 (1H, m), 4.59 (2H, t, J = 4.9 Hz), 4.22 (2H, d, J = 7.1 Hz), 3.48- 3.40 (4H, m), 2.39 (3H, s), 2.19-2.13 (1H, m). 664 (optically active form)

¹H-NMR (CDCl₃) δ: 7.72-7.68 (1H, m), 7.66-7.64 (1H, m), 7.59-7.55 (2H, m), 7.31- 7.21 (3H, m), 7.15-7.13 (1H, m), 6.32-6.29 (1H, m), 4.37-4.31 (1H, m), 4.21- 4.10 (4H, m), 3.23-3.07 (1H, m), 2.90-2.71 (2H, m), 1.95 (3H, d, J = 1.3 Hz), 1.93 (3H, d, J = 1.3 Hz). 665 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.94 (1H, d, J = 0.7 Hz), 7.63- 7.59 (2H, m), 7.61 (1H, d, J = 0.7 Hz), 7.41-7.37 (2H, m), 7.32-7.22 (2H, m), 7.15 (1H, s), 7.10 (1H, d, J = 1.5 Hz), 4.97-4.92 (2H, m), 4.39-4.32 (1H, m), 3.86-3.79 (4H, m), 2.58- 2.48 (2H, m), 1.92-1.82 (1H, m), 0.93 (3H, d, J = 6.6 Hz), 0.91 (6H, d, J = 6.6 Hz).

TABLE 1-98 compound No. structural formula NMR 666

¹H-NMR (DMSO-D₆) δ: 7.94 (1H, d, J = 0.7 Hz), 7.63- 7.59 (2H, m), 7.61 (1H, d, J = 0.7 Hz), 7.44-7.41 (1H, m), 7.39-7.35 (1H, m), 7.32-7.22 (2H, m), 7.16 (1H, s), 7.14 (1H, d, J = 1.62 Hz), 4.98-4.94 (2H, m), 4.38-4.32 (1H, m), 3.86-3.77 (4H, m), 2.65- 2.59 (2H, m), 1.53-1.47 (2H, m), 0.96 (9H, s). 667 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.33 (1H, d, J = 0.7 Hz), 8.13 (1H, br s), 7.98 (1H, d, J = 0.9 Hz), 7.92 (1H, d, J = 7.5 Hz), 7.84 (1H, br s), 7.73 (1H, br s), 7.70 (1H, d, J = 1.8 Hz), 7.65 (1H, d, J = 7.3 Hz), 7.49-7.44 (1H, m), 7.40-7.35 (1H, m), 7.30 (1H, s), 3.98 (2H, d, J = 7.3 Hz), 1.92-1.80 (1H, m), 1.73-1.50 (5H, m), 1.26-1.10 (3H, m), 1.03- 0.91 (2H, m). 668 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.27 (1H, s), 7.92 (1H, s), 7.80 (1H, d, J = 7.9 Hz), 7.74 (1H, s), 7.72 (1H, s), 7.66 (1H, d, J = 7.4 Hz), 7.53- 7.48 (1H, m), 7.40-7.34 (1H, m), 7.21 (1H, s), 5.46 (1H, t, J = 5.3 Hz), 4.91- 4.82 (2H, m), 3.98 (2H, d, J = 7.2 Hz), 1.91-1.79 (1H, m), 1.72-1.50 (5H, m), 1.26-1.11 (3H, m), 1.03- 0.92 (2H, m). 669 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.94 (1H, d, J = 0.7 Hz), 7.63- 7.59 (1H, m), 7.61 (1H, d, J = 0.7 Hz), 7.45-7.41 (1H, m), 7.39-7.35 (1H, m), 7.32-7.22 (2H, m), 7.16 (1H, s), 7.14 (1H, d, J = 1.6 Hz), 4.98-4.93 (2H, m), 4.38-4.32 (1H, m), 3.86- 3.78 (4H, m), 2.65-2.59 (2H, m), 1.54-1.47 (2H, m), 0.96 (9H, s).

TABLE 1-99 compound No. structural formula NMR 670

¹H-NMR (DMSO-D₆) δ: 12.17 (1H, br s), 7.97 (1H, s), 7.65-7.58 (2H, m), 7.43 (1H, s), 7.32-7.22 (3H, m), 7.17 (1H, s), 7.13-7.12 (1H, m), 4.24 (2H, t, J = 6.7 Hz), 2.38 (3H, s), 2.27 (2H, t, J = 7.4 Hz), 2.13- 2.04 (2H, m). 671

¹H-NMR (DMSO-D₆) δ: 8.14- 8.10 (1H, m), 8.07-8.01 (3H, m), 7.73-7.69 (1H, m), 7.63-7.57 (1H, m), 7.56- 7.49 (2H, m). 672 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8,03 (1H, d, J = 0.4 Hz), 7.67- 7.63 (1H, m), 7.66 (1H, d, J = 0.9 Hz), 7.42-7.38 (1H, m), 7.40 (1H, s), 7.36-7.32 (3H, m), 7.18-7.14 (1H, m), 3.96 (3H, s). 673 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.05 (1H, d, J = 0.7 Hz), 7.68 (1H, d, J = 0.7 Hz), 7.65- 7.62 (1H, m), 7.44-7.42 (1H, m), 7.40-7.36 (2H, m), 7.35-7.26 (2H, m), 7.21- 7.17 (1H, m), 4.98-4.93 (2H, m), 3.84-3.79 (2H, m), 3.76-3.70 (2H, m), 1.52 (3H, s). 674 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, s), 7.67 (1H, s), 7.66-7.63 (1H, m), 7.44- 7.38 (3H, m), 7.36-7.27 (2H, m), 7.21-7.17 (1H, m), 4.79 (1H, s), 4.13 (2H, s), 1.15 (6H, s). 675 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.08 (1H, d, J = 0.5 Hz), 7.68 (1H, s), 7.66-7.62 (1H, m), 7.41-7.36 (3H, m), 7.36- 7.28 (2H, m), 7.23-7.18 (1H, m), 5.08 (1H, t, J = 5.6 Hz), 3.66 (2H, d, J = 5.6 Hz), 1.55 (6H, s).

TABLE 1-100 compound No. structural formula NMR 676 (optically active form)

¹H-NMR (CDCl₃) δ: 7.70-7.66 (1H, m), 7.54-7.48 (2H, m), 7.32-7.21 (4H, m), 7.11- 7.09 (1H, m), 4.00 (3H, s), 2.80-2.74 (2H, m), 1.86- 1.80 (2H, m), 1.31 (6H, s). 677 (optically active form)

¹H-NMR (CDCl₃) δ: 7.71-7.67 (1H, m), 7.59-7.57 (2H, m), 7.54-7.52 (1H, m), 7.30- 7.23 (3H, m), 7.13-7.11 (1H, m), 4.37-4.32 (2H, m), 4.13-4.07 (2H, m), 3.05 (1H, s), 3.00-2.95 (1H, m), 2.82-2.74 (2H, m), 1.87- 1.80 (2H, m), 1.31 (7H, s). 678 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, s), 7.63-7.57 (1H, m), 7.61 (1H, s), 7.31-7.20 (3H, m), 7.22 (1H, s), 7.16-7.11 (1H, m), 6.82- 6.80 (1H, m), 4.64 (1H, t, J = 5.4 Hz), 3.95 (3H, s), 3.77 (2H, s), 3.29 (2H, d, J = 5.3 Hz), 0.94 (6H, s). 679 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.97 (1H, s), 7.63 (1H, s), 7.61-7.57 (1H, m), 7.33- 7.30 (1H, m), 7.27-7.24 (2H, m), 7.22 (1H, s), 7.15-7.13 (1H, m), 6.83- 6.81 (1H, m), 4.97 (1H, t, J = 5.3 Hz), 4.65 (1H, t, J = 5.4 Hz), 4.25 (2H, t, J = 5.6 Hz), 3.85-3.80 (2H, m), 3.77 (2H, s), 3.29 (2H, d, J = 5.3 Hz), 0.95 (6H, s). 680 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, s), 7.63-7.59 (2H, m), 7.32-7.26 (3H, m), 7.26- 7.24 (1H, m), 7.23 (1H, s), 6.91-6.89 (1H, m), 4.96 (1H, t, J = 5.7 Hz), 3.95 (3H, s), 3.41 (2H, d, J = 5.6 Hz), 1.25 (3H, s), 1.24 (3H, s). 681 (optically active form)

¹H-NMR (CDCl₃) δ: 7 .71-7.67 (1H, m), 7.58 (2H, s), 7.34-7.32 (1H, m), 7.30- 7.22 (3H, m), 6.90-6.89 (1H, m), 4.36-4.33 (2H, m), 4.13-4.09 (2H, m), 3.65- 3.61 (2H, m), 3.14 (1H, s), 3.03-2.98 (1H, m), 2.18- 2.13 (1H, m), 1.36 (3H, s), 1.33 (3H, s).

TABLE 1-101 compound No. structural formula NMR 682 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.70- 7.65 (1H, m), 7.57-7.53 (1H, m), 7.53-7.48 (3H, m), 7.46-7.38 (3H, m), 4.94- 4.89 (2H, m), 3.83-3.74 (4H, m), 3.23-3.19 (1H, m). 683 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.96- 7.94 (1H, m), 7.64-7.59 (1H, m), 7.58 (1H, d, J = 0.9 Hz), 7.45-7.42 (1H, m), 7.32-7.27 (3H, m), 7.16 (1H, s), 7.12-7.09 (1H, m), 4.53 (1H, t, J = 5.4 Hz), 3.95 (3H, s), 3.17 (2H, d, J = 5.5 Hz), 2.63-2.55 (2H, m), 1.53-1.44 (2H, m), 0.88 (6H, s). 684 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.94 (1H, d, J = 0.7 Hz), 7.64- 7.59 (1H, m), 7.61 (1H, d, J = 0.9 Hz), 7.45-7.42 (1H, m), 7.37-7.24 (3H, m), 7.16 (1H, s), 7.13-7.10 (1H, m), 4.96 (1H, t, J = 5.2 Hz), 4.53 (1H, t, J = 5.4 Hz), 4.25 (2H, t, J = 5.6 Hz), 3.85-3.79 (2H, m), 3.17 (2H, d, J = 5.3 Hz), 2.63- 2.56 (2H, m), 1.54-1.45 (2H, m), 0.88 (6H, s). 685 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.11- 8.05 (1H, m), 7.91-7.86 (1H, m), 7.83-7.78 (1H, m), 7.75-7.70 (1H, m), 7.63 (1H, s), 7.51-7.45 (2H, m), 4.91-4.86 (2H, m), 3.89- 3.75 (4H, m), 3.31-3.23 (1H, m). 686 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.96 (1H, s), 7.64-7.58 (1H, m), 7.61 (1H, s), 7.44-7.35 (2H, m), 7.33-7.22 (2H, m), 7.18-7.13 (2H, m), 4.96 (2H, t, J = 5.4 Hz), 3.85- 3.78 (2H, m), 3.77-3.70 (2H, m), 2.39 (3H, s), 1.52 (3H, s).

TABLE 1-102 compound No. structural formula NMR 687 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.10 (1H, d, J = 0.7 Hz), 7.67 (1H, d, J = 0.7 Hz), 7.66- 7.62 (1H, m), 7.47-7.44 (1H, m), 7.40-7.37 (2H, m), 7.36-7.28 (2H, m), 7.22- 7.18 (1H, m), 4.78 (1H, s), 1.63 (3H, s), 1.63 (3H, s), 1.08 (3H, s), 1.07 (3H, s). 688 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, s), 7.63-7.57 (1H, m), 7.61 (1H, s), 7.30-7.24 (3H, m), 7.22 (1H, s), 7.17-7.14 (1H, m), 6.84- 6.80 (1H, m), 4.66 (1H, br s), 3.95 (3H, s), 3.78 (2H, s), 1.22 (3H, s), 1.22 (3H, s). 689 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7-97 (1H, d, J = 0.7 Hz), 7.64 (1H, d, J = 0.7 Hz), 7.61- 7.56 (1H, m), 7.34-7.30 (1H, m), 7.29-7.23 (2H, m), 7.21 (1H, s), 7.17-7.13 (1H, m), 6.85-6.82 (1H, m), 4.96 (1H, t, J = 5.3 Hz), 4.65 (1H, s), 4.25 (2H, t, J = 5.6 Hz), 3.84-3.80 (2H, m), 3.79 (2H, s), 1.22 (3H, s), 1.22 (3H, s). 690 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, s), 7.64-7.59 (2H, m), 7.44-7.40 (1H, m), 7.33- 7.21 (3H, m), 7.17 (1H, s), 7.15-7.10 (2H, m), 4.27 (2H, t, J = 6.5 Hz), 3.02- 2.95 (2H, m), 2.92-2.89 (3H, m), 2.37 (3H, s), 2.10-2.01 (2H, m). 691 (optically active form)

¹H-NMR (DMSO-D₆) δ: 16.09 (1H, br s), 8.01 (1H, d, J = 0.7 Hz), 7.65-7.60 (1H, m), 7.63 (1H, d, J = 0.7 Hz), 7.45-7.42 (1H, m), 7.33-7.23 (3H, m), 7.20- 7.16 (1H, m), 7.15-7.11 (1H, m), 4.32 (2H, t, J = 6.6 Hz), 2.93 (2H, t, J = 7.7 Hz), 2.39 (3H, s), 2.36-2.27 (2H, m).

TABLE 1-103 compound No. structural formula NMR 692 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.13- 8.10 (1H, m), 7.77-7.73 (1H, m), 7.67-7.63 (1H, m), 7.44-7.40 (2H, m), 7.38- 7.28 (3H, m), 7.18-7.14 (1H, m), 6.83-6.78 (1H, m), 4.61-4.48 (2H, m), 4.42- 4.31 (1H, m). 693 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.17 (1H, s), 7.72 (1H, s), 7.66-7.62 (1H, m), 7.46- 7.38 (3H, m), 7.36-7.27 (3H, m), 7.25-7.20 (1H, m), 7.02 (1H, br s), 1.80 (3H, s), 1.79 (3H, s). 694 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.16 (1H, d, J = 0.7 Hz), 7.73 (1H, d, J = 0.4 Hz), 7.66- 7.63 (1H, m), 7.52-7.47 (1H, m), 7.43-7.38 (3H, m), 7.36-7.29 (2H, m), 7.24- 7.20 (1H, m), 2.63 (3H, d, J = 4.6 Hz), 1.79 (3H, s), 1.79 (3H, s). 695 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.23 (1H, s), 7.80 (1H, s), 7.68-7.63 (1H, m), 7.44- 7.40 (2H, m), 7.37-7.31 (3H, m), 7.25-7.21 (1H, m), 3.00-2.20 (6H, m), 1.77 (3H, s), 1.77 (3H, s). 696 (optically active form)

¹H-NMR (CDCl₃) δ: 7.69-7.65 (1H, m), 7.54 (1H, s), 7.51-7.49 (2H, m), 7.28- 7.19 (3H, m), 7.10-7.07 (1H, m), 4.34-4.29 (2H, m), 4.31 (3H, s), 3.20 (1H, s), 2.94 (2H, t, J = 7.2 Hz), 2.46-2.38 (2H, m), 2.42 (3H, s).

TABLE 1-104 compound No. structural formula NMR 697 (optically active form)

¹H-NMR (CDCl₃) δ: 7.69-7.66 (1H, m), 7.63 (1H, s), 7.55 (1H, s), 7.51-7.49 (1H, m), 7.31-7.20 (3H, m), 7.09- 7.08 (1H, m), 4.40 (2H, t, J = 6.4 Hz), 4.01 (3H, s), 2.93 (2H, t, J = 7.1 Hz), 2.78 (1H, s), 2.58-2.51 (2H, m), 2.43 (3H, s). 698 (optically active form)

¹H-NMR (CDCl₃) δ: 7.72-7.67 (1H, m), 7.56-7.52 (1H, m), 7.48 (1H, s), 7.45 (1H, s), 7.33-7.21 (3H, m), 7.11 (1H, s), 3.99 (3H, s), 3.38 (1H, s), 2.84 (1H, d, J = 13.0 Hz), 2.80 (1H, d, J = 13.2 Hz), 1.43 (1H, br s), 1.28 (3H, s), 1.25 (3H, s). 699 (optically active form)

¹H-NMR (CDCl₃) δ: 7.71-7.67 (1H, m), 7.56 (1H, s), 7.53 (1H, s), 7.47-7.44 (1H, m), 7.31-7.20 (3H, m), 7.04- 7.02 (1H, m), 4.35-4.31 (2H, m), 4.11-4.07 (2H, m), 3.10 (1H, br s), 2.96-2.91 (1H, m), 2.56 (2H, s), 0.95 (9H, s). 700 (optically active form)

¹H-NMR (CDCl₃) δ: 7.94-7.92 (1H, m), 7.77-7.72 (1H, m), 7.64 (1H, s), 7.63 (1H, s), 7.59-7.57 (1H, m), 7.44- 7.30 (3H, m), 4.40-4.34 (2H, m), 4.15-4.06 (2H, m), 3.19 (1H, br s), 2.83 (1H, t, J = 5.8 Hz). 701 (optically active form)

¹H-NMR (CDCl₃) δ: 8.24-8.22 (1H, m), 7.89-7.86 (1H, m), 7.77-7.73 (1H, m), 7.63 (2H, s), 7.41-7.36 (2H, m), 7.32-7.27 (1H, m), 4.38- 4.35 (2H, m), 4.14-4.09 (2H, m), 3.23 (1H, br s), 2.94 (1H, t, J = 5.9 Hz), 2.65 (3H, s).

TABLE 1-105 compound No. structural formula NMR 702 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, d, J = 0.7 Hz), 7.65- 7.58 (2H, m), 7.62 (1H, d, J = 0.7 Hz), 7.42-7.24 (5H, m), 7.19 (1H, s), 4.98-4.92 (2H, m), 3.84-3.79 (2H, m), 3.77-3.70 (2H, m), 1.52 (3H, s). 703 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.05 (1H, d, J = 0.7 Hz), 7.70 (1H, d, J = 0.7 Hz), 7.65- 7.61 (1H, m), 7.51-7.47 (1H, m), 7.40-7.36 (2H, m), 7.35-7.30 (1H, m), 7.29- 7.24 (1H, m), 7.21-7.17 (1H, m), 4.83 (3H, t, J = 5.4 Hz), 3.90 (6H, d, J = 5.6 Hz). 704 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.04 (1H, d, J = 0.7 Hz), 7.69 (1H, d, J = 0.7 Hz), 7.66- 7.62 (1H, m), 7.42-7.37 (2H, m), 7.38 (1H, s), 7.36-7.31 (1H, m), 7.29- 7.25 (1H, m), 7.21-7.16 (1H, m), 4.90-4.86 (2H, m), 3.91-3.81 (4H, m), 1.92 (2H, q, J = 7.4 Hz), 0.75 (3H, t, J = 7.5 Hz). 705 (optically active form)

¹H-NMR (DMSO-D₆) δ: 8.01 (1H, s), 7.68 (1H, s), 7.66-7.61 (1H, m), 7.45- 7.37 (2H, m), 7.36-7.27 (3H, m), 7.20-7.15 (1H, m), 4.66-4.52 (3H, m), 3.42- 3.29 (2H, m), 3.27-3.15 (2H, m), 2.13-2.01 (2H, m), 1.99-1.86 (2H, m). 706 (optically active form)

¹H-NMR (DMSO-D₆) δ: 7.98 (1H, d, J = 0.7 Hz), 7.65- 7.59 (2H, m), 7.64 (1H, s), 7.49-7.46 (1H, m), 7.41- 7.36 (1H, m), 7.35-7.30 (2H, m), 7.28-7.23 (1H, m), 7.19 (1H, s), 4.82 (3H, t, J = 5.4 Hz), 3.92 (6H, d, J = 5.5 Hz).

TABLE 1-106 com- pound No. structural formula NMR 707 (op- tically active form)

¹H-NMR (DMSO-D₆) δ: 7.96 (1H, d, J = 0.7 Hz), 7.63-7.59 (1H, m), 7.62 (1H, d, J = 0.7 Hz), 7.46-7.40 (2H, m), 7.31-7.21 (2H, m), 7.14 (2H, s), 4.82 (3H, t, J = 5.6 Hz), 3.91 (6H, d, J = 5.6 Hz), 2.39 (3H, s).

Among these compounds, compound Nos. 42-44, 56, 57, 72, 73 and 143 are Reference Examples.

Among the above-mentioned optically active compounds, the structural formulas of the compounds having a specified absolute configuration are shown in the following Table 2-1 to 2-11.

TABLE 2-1 compound structural formula No. (absolute configuration) 520

526

529

531

532

TABLE 2-2 compound structural formula No. (absolute configuration) 533

534

537

538

539

TABLE 2-3 compound structural formula No. (absolute configuration) 543

544

545

546

548

TABLE 2-4 compound structural formula No. (absolute configuration) 549

550

551

565

566

TABLE 2-5 compound structural formula No. (absolute configuration) 574

575

576

595

605

TABLE 2-6 compound structural formula No. (absolute configuration) 606

607

610

663

TABLE 2-7 compound structural formula No. (absolute configuration) 670

672

673

674

675

TABLE 2-8 compound structural formula No. (absolute configuration) 682

685

686

687

690

TABLE 2-9 compound structural formula No. (absolute configuration) 691

692

693

694

TABLE 2-10 compound structural formula No. (absolute configuration) 695

696

697

702

TABLE 2-11 compound structural formula No. (absolute configuration) 703

704

705

706

707

The Formulation Examples of the present invention include the following preparations, which are not to be construed as limitative.

Formulation Example 1 Production of Capsule

1) compound of Example 1 30 mg 2) microcrystalline cellulose 10 mg 3) lactose 19 mg 4) magnesium stearate  1 mg

1), 2), 3) and 4) are mixed and filled in a gelatin capsule.

Formulation Example 2 Production of Tablet

1) compound of Example 1 10 g 2) lactose 50 g 3) cornstarch 15 g 4) carmellose calcium 44 g 5) magnesium stearate  1 g

The total amount of 1), 2) and 3), and 30 g of 4) are kneaded with water, dried in vacuo and sieved. The sieved powder is mixed with 14 g of 4) and 1 g of 5) and the mixture is tableted by a tableting machine, whereby 1000 tablets containing 10 mg of the compound of Example 1 per tablet are obtained.

Experimental Example 1 Inhibitory Action of PDHK Activity In Vitro

The inhibitory action of PDHK activity was indirectly evaluated by performing a kinase reaction in the presence of a test compound and measuring the residual PDH activity.

In the case of human PDHK2 (hPDHK2, Genbank Accession No. NM_(—)002611), modified hPDHK2 cDNA wherein FLAG-Tag sequence is added to the N terminal by a polymerase linkage reaction was prepared based on hPDHK2 cDNA clone (pReceiver-M01/PDK2-GeneCopoeia), and cloned into a vector (pET17b-Novagen). The recombinant construct was transformed into Escherichia coli (DH5α-TOYOBO). The recombinant clones were identified, plasmid DNA was isolated and subjected to the DNA sequence analysis. One clone which had the expected nucleic acid sequence was selected for expression work.

For expression of hPDHK2 activity, Escherichia coli strain BL21(DE3) cells (Novagen) were transformed with the pET17b vector containing modified hPDHK2 cDNA. Escherichia coli were grown to an optical density 0.6 (600 nmol/L) at 30° C. Protein expression was induced by the addition of 500 μmol/L isopropyl-β-thiogalactopyranoside. Escherichia coli were cultured at 30° C. for 5 hr and harvested by centrifugation. Resuspension of the Escherichia coli paste was disrupted by a microfluidizer. FLAG-Tagged protein was separated using FLAG affinity gel (Sigma). The gel was washed with 20 mmol/L N-(2-hydroxyethyl)piperazine-N′-2-ethanesulfonic acid-sodium hydroxide (HEPES-NaOH), 500 mmol/L sodium chloride, 1% ethylene glycol, and 0.1% Pluronic F-68 (pH 8.0), and the binding protein was eluted with 20 mmol/L HEPES-NaOH, 100 μg/mL FLAG peptide, 500 mmol/L sodium chloride, 1% ethylene glycol, and 0.1% Pluronic F-68 (pH 8.0). The eluted fractions containing FLAG-Tagged protein were pooled, dialyzed against 20 mmol/L HEPES-NaOH, 150 mmol/L sodium chloride, 0.5 mmol/L ethylenediaminetetraacetic acid (EDTA), 1% ethylene glycol, and 0.1% Pluronic F-68 (pH 8.0), and preserved at −80° C. During the assay, the hPDHK2 enzyme concentration was set to the minimal concentration at which PDH is inhibited the most.

0.05 U/mL PDH (porcine heart PDH complex, Sigma P7032) and 1.6 μg/mL hPDHK2 were mixed in a buffer (50 mmol/L 3-morpholinopropanesulfonic acid (pH 7.0), 20 mmol/L dipotassium hydrogen phosphate, 60 mmol/L potassium chloride, 2 mmol/L magnesium chloride, 0.4 mmol/L EDTA, and 0.2% Pluronic F-68, 2 mmol/L dithiothreitol), the mixture was incubated at 4° C. overnight to give PDH/hPDHK2 complex. The test compound was diluted with dimethyl sulfoxide (DMSO). PDH/hPDHK2 complex (20 μL), test compound (1.5 μL) and 3.53 μmol/L ATP (diluted with buffer, 8.5 μL) were added to a half area 96 well UV-transparent microplate (Corning 3679), and PDHK reaction was performed at room temperature for 45 min. Instead of the test compound, DMSO (1.5 μL) was added to a control well. DMSO (1.5 μL) was added instead of the test compound to a blank well for the measurement of the maximum rate of PDH reaction, and hPDHK2 was not added. Than, 10 μL of substrates (5 mmol/L sodium pyruvate, 5 mmol/L Coenzyme A, 12 mmol/L NAD, and 5 mmol/L thiamine pyrophosphate, diluted with buffer) was added. The mixture was incubated at room temperature for 90 min, and the residual PDH activity was measured. The absorbance at 340 nm before and after PDH reaction was measured on a microplate reader to detect NADH produced by the PDH reaction. The PDHK inhibitory rate (%) of the test compound was calculated from the formula [{(PDH activity of test compound−PDH activity of control)/PDH activity of blank−PDH activity of control)}×100]. The IC₅₀ value was calculated from the concentrations of the test compound at two points enclosing 50% inhibition of the PDHK activity.

The obtained results are shown in the following Table 3-1-Table 3-29. In the Tables, the inhibitory activity of the compound is shown as follows. +++: IC₅₀ (μmol/L) of less than 0.1 μmol/L, ++: not less than 0.1 μmol/L and less than 1 μmol/L, +: not less than 1 μmol/L. The compounds for which the measurement was not conducted is shown as ND.

TABLE 3-1 PDHK inhibitory activity compound No. IC₅₀ (μmol/L) 1 + 2.208 2 + 2.286 3 + 1.567 4 + 2.292 5 + 1.169 6 + 2.294 7 + 1.435 8 + 45.643 9 + 20.040 10 + 30.793 11 + 6.792 12 + 5.495 13 + 15.876 14 + 56.574 15 + 16.312 16 + 19.303 17 + 13.871 18 ++ 0.457 19 + >100 20 + 3.497 21 ++ 0.302 22 + 16.691 23 ++ 0.571 24 + >100 25 + 30.863

TABLE 3-2 PDHK inhibitory activity compound No. IC₅₀ (μmol/L) 26 + 17.596 27 ++ 0.848 28 + 2.815 29 + 5.739 30 + 8.609 31 + 1.353 32 + >100 33 + 1.814 34 + 33.181 35 + >100 36 ++ 0.626 37 + 3.959 38 + 12.022 39 + 4.522 40 + 2.469 41 + 68.593 42 + 5.564 43 + 3.920 44 + >100 45 ++ 0.247 46 + 6.486 47 + 4.909 48 ++ 0.639 49 + 1.787 50 ++ 0.100

TABLE 3-3 PDHK inhibitory activity compound No. IC₅₀ (μmol/L) 51 + 2.590 52 + 4.010 53 ++ 0.567 54 + 21.913 55 + 19.786 56 + >100 57 + 5.621 58 ++ 0.195 59 ++ 0.772 60 + 2.037 61 ++ 0.294 62 + 15.728 63 + 8.484 64 + 17.963 65 + >100 66 + 66.305 67 + 4.199 68 ++ 0.624 69 + 16.015 70 + 2.213 71 + 10.220 72 + 4.424 73 + 4.814 74 + 3.317 75 + 6.783

TABLE 3-4 PDHK inhibitory activity compound No. IC₅₀ (μmol/L) 76 + 1.754 77 + 2.497 78 + 1.358 79 ++ 0.696 80 + 8.245 81 + 2.762 82 + 67.348 83 + 1.141 84 + 42.066 85 + 23.099 86 ++ 0.378 87 ++ 0.669 88 + 2.526 89 + 2.147 90 ++ 0.474 91 +++ 0.072 92 ++ 0.405 93 + 29.507 94 +++ 0.049 95 + 7.831 96 + 6.568 97 ++ 0.849 98 + 2.423 99 ++ 0.718 100 + 6.148

TABLE 3-5 PDHK inhibitory activity compound No. IC₅₀ (μmol/L) 101 + 10.296 102 ++ 0.323 103 ++ 0.151 104 ++ 0.279 105 ++ 0.259 106 ++ 0.461 107 + 2.613 108 ++ 0.462 109 + 1.317 110 + 2.488 111 + >10 112 + 1.230 113 + 1.113 114 +++ 0.051 115 ++ 0.417 116 ++ 0.601 117 ++ 0.909 118 ++ 0.839 119 + 1.005 120 ++ 0.174 121 + 3.676 122 +++ 0.049 123 ++ 0.877 124 ++ 0.736 125 ++ 0.227

TABLE 3-6 compound PDHK inhibitory activity No. IC₅₀ (μmol/L) 126 + >10 127 + >10 128 + 2.395 129 ++ 0.864 130 + >10 131 + >10 132 ++ 0.694 133 + 2.498 134 + >10 135 + >1 136 +++ 0.025 137 + 1.007 138 + >10 139 + >10 140 + 2.402 141 +++ 0.077 142 ++ 0.543 143 + >10 144 + 1.122 145 + 1.382 146 ++ 0.213 147 + 1.729 148 + 8.450 149 + 1.220 150 + 6.838

TABLE 3-7 PDHK inhibitory activity compound No. IC₅₀ (μmol/L) 151 + 5.213 152 +++ 0.054 153 +++ 0.036 154 ++ 0.309 155 ++ 0.805 156 ++ 0.464 157 ++ 0.358 158 ++ 0.221 159 ++ 0.318 160 + 2.538 161 + 2.113 162 + 2.886 163 ++ 0.232 164 + 2.747 165 ++ 0.957 166 + 5.899 167 + 1.947 168 + >10 169 + 7.362 170 + 6.735 171 ++ 0.951 172 ++ 0.779 173 + >10 174 +++ 0.066 175 ++ 0.517

TABLE 3-8 compound PDHK inhibitory activity No. IC₅₀ (μmol/L) 176 + 8.013 177 + 9.189 178 + >10 179 + 1.340 180 + >10 181 + 1.514 182 + >10 183 + >10 184 + >10 185 +++ 0.053 186 + 5.906 187 + 2.478 188 ++ 0.383 189 + 6.000 190 + >10 191 ++ 0.216 192 ++ 0.182 193 ++ 0.560 194 ++ 0.368 195 + 5.485 196 ++ 0.475 197 ++ 0.298 198 ++ 0.126 199 ++ 0.182 200 ++ 0.236

TABLE 3-9 compound PDHK inhibitory activity No. IC₅₀ (μmol/L) 201 ++ 0.162 202 ++ 0.247 203 ++ 0.423 204 + >10 205 ++ 0.707 206 + 2.240 207 ++ 0.998 208 ++ 0.677 209 ++ 0.281 210 + 1.327 211 + 1.012 212 ++ 0.685 213 ++ 0.173 214 ++ 0.345 215 + 4.599 216 + 2.565 217 + 5.329 218 + 1.837 219 + >10 220 ++ 0.488 221 + >10 222 + 5.391 223 + 2.327 224 ++ 0.214 225 ++ 0.619

TABLE 3-10 compound PDHK inhibitory activity No. IC₅₀ (μmol/L) 226 + 1.142 227 + 1.048 228 + 2.192 229 ++ 0.552 230 + 3.712 231 + 3.607 232 + 1.988 233 ++ 0.142 234 +++ 0.058 235 ++ 0.803 236 ++ 0.355 237 + 1.999 238 ++ 0.252 239 ++ 0.178 240 ++ 0.149 241 +++ 0.098 242 +++ 0.086 243 +++ 0.075 244 + 2.929 245 ++ 0.190 246 ++ 0.809 247 ++ 0.547 248 + 1.019 249 ++ 0.719 250 + 1.609

TABLE 3-11 compound PDHK inhibitory activity No. IC₅₀ (μmol/L) 251 + >10 252 + 1.273 253 + 1.947 254 + 1.131 255 + 1.078 256 + 1.003 257 ++ 0.567 258 + 2.625 259 + 1.386 260 + 2.813 261 + 1.404 262 + 1.365 263 ++ 0.133 264 + 1.169 265 + 1.258 266 + 1.556 267 + 1.197 268 + >10 269 + 1.338 270 ++ 0.533 271 +++ 0.056 272 ++ 0.342 273 ++ 0.396 274 + 7.487 275 ++ 0.278

TABLE 3-12 compound PDHK inhibitory activity No. IC₅₀ (μmol/L) 276 + 1.013 277 ++ 0.125 278 ++ 0.862 279 + 1.849 280 + 1.514 281 + 1.000 282 ++ 0.226 283 ++ 0.571 284 + 1.168 285 +++ 0.020 286 +++ 0.017 287 + >10 288 ++ 0.635 289 ++ 0.641 290 ++ 0.793 291 + 5.826 292 + 2.571 293 + 4.947 294 ++ 0.710 295 ++ 0.861 296 ++ 0.180 297 + 3.034 298 ++ 0.177 299 ++ 0.235 300 ++ 0.114

TABLE 3-13 compound PDHK inhibitory activity No. IC₅₀ (μmol/L) 301 + 1.586 302 + 1.167 303 ++ 0.755 304 ++ 0.723 305 ++ 0.562 306 ++ 0.453 307 + 3.198 308 + 2.666 309 + >10 310 + >10 311 + 7.151 312 + 1.824 313 + >10 314 + >10 315 + 6.371 316 + 4.480 317 + 2.313 318 ++ 0.553 319 + 3.086 320 + 8.765 321 + 5.385 322 + 2.503 323 ++ 0.362 324 ++ 0.203 325 + 1.080

TABLE 3-14 compound PDHK inhibitory activity No. IC₅₀ (μmol/L) 326 ++ 0.303 327 + 2.941 328 +++ 0.078 329 +++ 0.066 330 ++ 0.125 331 + 1.415 332 ++ 0.912 333 ++ 0.924 334 ++ 0.674 335 +++ 0.080 336 + >10 337 ++ 0.499 338 + >1 339 ++ 0.177 340 + 1.594 341 +++ 0.079 342 +++ 0.047 343 +++ 0.053 344 + >1 345 ++ 0.121 346 ++ 0.200 347 +++ 0.088 348 ++ 0.634 349 ++ 0.126 350 ++ 0.152

TABLE 3-15 compound PDHK inhibitory activity No. IC₅₀ (μmol/L) 351 ++ 0.168 352 ++ 0.109 353 + 7.398 354 +++ 0.071 355 +++ 0.040 356 +++ 0.053 357 + 1.939 358 +++ 0.034 359 ++ 0.187 360 ++ 0.548 361 ++ 0.436 362 + 1.077 363 +++ 0.047 364 ++ 0.178 365 + 1.327 366 + 2.170 367 + >1 368 ++ 0.180 369 +++ 0.081 370 ++ 0.114 371 ++ 0.617 372 ++ 0.564 373 +++ 0.049 374 +++ 0.049 375 +++ 0.050

TABLE 3-16 compound PDHK inhibitory activity No. IC₅₀ (μmol/L) 376 +++ 0.085 377 ++ 0.189 378 ++ 0.703 379 ++ 0.351 380 + 1.490 381 ++ 0.495 382 ++ 0.863 383 + 1.225 384 ++ 0.219 385 ++ 0.234 386 +++ 0.089 387 +++ 0.063 388 +++ 0.063 389 ++ 0.822 390 ++ 0.954 391 ++ 0.485 392 ++ 0.200 393 ++ 0.176 394 +++ 0.058 395 ++ 0.699 396 ++ 0.627 397 ++ 0.424 398 ++ 0.119 399 ++ 0.149 400 + 7.077

TABLE 3-17 compound PDHK inhibitory activity No. IC₅₀ (μmol/L) 401 ++ 0.554 402 + >10 403 + >10 404 ++ 0.195 405 + 6.377 406 +++ 0.025 407 +++ 0.031 408 +++ 0.065 409 +++ 0.067 410 ++ 0.154 411 +++ 0.066 412 +++ 0.022 413 + 1.230 414 +++ 0.032 415 + 9.190 416 ++ 0.104 417 + >1 418 + 6.065 419 ++ 0.504 420 ++ 0.225 421 ++ 0.233 422 +++ 0.023 423 +++ 0.021 424 +++ 0.023 425 +++ 0.021

TABLE 3-18 compound PDHK inhibitory activity No. IC₅₀ (μmol/L) 426 +++ 0.024 427 +++ 0.020 428 +++ 0.025 429 +++ 0.019 430 +++ 0.064 431 ++ 0.250 432 ++ 0.247 433 ++ 0.388 434 ++ 0.561 435 +++ 0.039 436 +++ 0.065 437 +++ 0.060 438 ++ 0.112 439 +++ 0.034 440 +++ 0.032 441 +++ 0.036 442 +++ 0.040 443 + 1.152 444 + 3.934 445 ++ 0.605 446 ++ 0.565 447 ++ 0.202 448 ++ 0.381 449 +++ 0.047 450 ++ 0.442

TABLE 3-19 compound PDHK inhibitory activity No. IC₅₀ (μmol/L) 451 ++ 0.102 452 + 2.719 453 +++ 0.028 454 +++ 0.064 455 +++ 0.026 456 +++ 0.045 457 +++ 0.030 458 +++ 0.039 459 ++ 0.185 460 +++ 0.030 461 +++ 0.030 462 + 5.979 463 +++ 0.047 464 +++ 0.042 465 +++ 0.061 466 +++ 0.055 467 +++ 0.018 468 ++ 0.327 469 ++ 0.193 470 ++ 0.168 471 +++ 0.026 472 ++ 0.184 473 +++ 0.090 474 +++ 0.019 475 +++ 0.020

TABLE 3-20 compound PDHK inhibitory activity No. IC₅₀ (μmol/L) 476 +++ 0.053 477 +++ 0.018 478 ++ 0.433 479 + >10 480 ++ 0.553 481 ++ 0.251 482 +++ 0.040 483 ++ 0.542 484 +++ 0.024 485 ++ 0.117 486 +++ 0.055 487 +++ 0.064 488 +++ 0.052 489 +++ 0.022 490 ++ 0.223 491 +++ 0.020 492 +++ 0.040 493 +++ 0.039 494 +++ 0.044 495 ++ 0.119 496 +++ 0.023 497 +++ 0.031 498 +++ 0.047 499 +++ 0.039 500 +++ 0.031

TABLE 3-21 compound PDHK inhibitory activity No. IC₅₀ (μmol/L) 501 +++ 0.032 502 +++ 0.048 503 +++ 0.045 504 +++ 0.019 505 +++ 0.046 506 +++ 0.030 507 +++ 0.026 508 +++ 0.048 509 +++ 0.051 510 +++ 0.062 511 +++ 0.056 512 +++ 0.038 513 +++ 0.032 514 +++ 0.058 515 +++ 0.038 516 ++ 0.110 517 +++ 0.057 518 +++ 0.054 519 ++ 0.418 520 + 3.330 521 +++ 0.036 522 +++ 0.061 523 +++ 0.048 524 +++ 0.087 525 ++ 0.677

TABLE 3-22 compound PDHK inhibitory activity No. IC₅₀ (μmol/L) 526 ++ 0.397 527 +++ 0.079 528 +++ 0.049 529 +++ 0.017 530 +++ 0.043 531 +++ 0.020 532 +++ 0.016 533 +++ 0.015 534 +++ 0.016 535 ++ 0.197 536 +++ 0.054 537 +++ 0.035 538 +++ 0.026 539 +++ 0.027 540 +++ 0.016 541 +++ 0.015 542 +++ 0.015 543 +++ 0.036 544 +++ 0.022 545 +++ 0.017 546 +++ 0.015 547 +++ 0.062 548 +++ 0.016 549 +++ 0.027 550 +++ 0.069

TABLE 3-23 compound PDHK inhibitory activity No. IC₅₀ (μmol/L) 551 ++ 0.109 552 +++ 0.017 553 +++ 0.018 554 +++ 0.020 555 + >1 556 +++ 0.053 557 +++ 0.077 558 +++ 0.081 559 + >1 560 ++ 0.970 561 +++ 0.050 562 +++ 0.059 563 +++ 0.063 564 ++ 0.105 565 +++ 0.018 566 +++ 0.021 567 + >1 568 +++ 0.083 569 +++ 0.044 570 ++ 0.110 571 +++ 0.050 572 ++ 0.109 573 +++ 0.018 574 +++ 0.052 575 +++ 0.036

TABLE 3-24 compound PDHK inhibitory activity No. IC₅₀ (μmol/L) 576 +++ 0.030 577 +++ 0.023 578 +++ 0.078 579 +++ 0.019 580 +++ 0.021 581 +++ 0.019 582 +++ 0.021 583 +++ 0.064 584 +++ 0.077 585 +++ 0.026 586 ++ 0.513 587 +++ 0.021 588 +++ 0.029 589 +++ 0.025 590 + 5.922 591 + >1 592 + >1 593 + >1 594 +++ 0.048 595 +++ 0.022 596 +++ 0.041 597 + >1 598 ++ 0.653 599 +++ 0.033 600 + >1

TABLE 3-25 compound PDHK inhibitory activity No. IC₅₀ (μmol/L) 601 + >1 602 + >1 603 ++ 0.228 604 +++ 0.035 605 +++ 0.019 606 +++ 0.028 607 +++ 0.045 608 + >1 609 + >1 610 +++ 0.041 611 ++ 0.329 612 +++ 0.047 613 +++ 0.076 614 +++ 0.037 615 ++ 0.105 616 ++ 0.192 617 +++ 0.084 618 +++ 0.056 619 +++ 0.033 620 +++ 0.065 621 +++ 0.065 622 +++ 0.033 623 ++ 0.133 624 +++ 0.014 625 + >1

TABLE 3-26 compound PDHK inhibitory activity No. IC₅₀ (μmol/L) 626 ++ 0.674 627 + >1 628 +++ 0.058 629 +++ 0.045 630 +++ 0.020 631 +++ 0.062 632 ++ 0.195 633 ++ 0.560 634 ++ 0.100 635 ++ 0.515 636 ++ 0.239 637 + >1 638 ++ 0.127 639 +++ 0.063 640 ++ 0.732 641 ++ 0.510 642 + >1 643 ++ 0.184 644 ++ 0.130 645 +++ 0.037 646 +++ 0.040 647 ++ 0.169 648 +++ 0.044 649 +++ 0.037 650 +++ 0.036

TABLE 3-27 compound PDHK inhibitory activity No. IC₅₀ (μmol/L) 651 +++ 0.025 652 +++ 0.036 653 +++ 0.037 654 +++ 0.055 655 +++ 0.073 656 ++ 0.172 657 +++ 0.020 658 +++ 0.071 659 +++ 0.016 660 +++ 0.017 661 +++ 0.059 662 +++ 0.034 663 +++ 0.018 664 +++ 0.015 665 +++ 0.023 666 +++ 0.027 667 +++ 0.015 668 +++ 0.017 669 +++ 0.017 670 ND ND 671 + 1.443 672 ND ND 673 +++ 0.022 674 +++ 0.030 675 ND ND

TABLE 3-28 compound PDHK inhibitory activity No. IC₅₀ (μmol/L) 676 ND ND 677 ND ND 678 ND ND 679 ND ND 680 ND ND 681 ND ND 682 +++ 0.079 683 ND ND 684 ND ND 685 ++ 0.338 686 ND ND 687 +++ 0.051 688 ND ND 689 ND ND 690 ND ND 691 +++ 0.030 692 ND ND 693 ND ND 694 ND ND 695 ND ND 696 ND ND 697 ND ND 698 ND ND 699 ND ND 700 ND ND

TABLE 3-29 compound PDHK inhibitory activity No. IC₅₀ (μmol/L) 701 ND ND 702 +++ 0.030 703 +++ 0.020 704 ND ND 705 ND ND 706 +++ 0.031 707 +++ 0.019

As is clear from the above-mentioned Experimental Example 1, the compound of the present invention has a PDHK activity inhibitory action.

Therefrom it is suggested that the compound of the present invention provides an effect of strong inhibition of PDHK.

Therefore, by inhibition of PDHK, the compound of the present invention effectively activates pyruvate dehydrogenase (PDH), and can provide an agent for the treatment or prophylaxis of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer and the like. Moreover, the compound of the present invention can provide an agent for the treatment or prophylaxis of diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), brain ischemia, cerebral apoplexy or pulmonary hypertension.

INDUSTRIAL APPLICABILITY

The present invention is useful for the treatment or prophylaxis and the like of diabetes (e.g., type 1 diabetes, type 2 diabetes etc.), insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer and the like. In addition, the present invention is useful for the treatment or prophylaxis and the like of diabetic complications (e.g., neuropathy, retinopathy, nephropathy, cataract etc.), brain ischemia, cerebral apoplexy or pulmonary hypertension. 

1-35. (canceled)
 36. The compound which is represented by the following formula, or a pharmaceutically acceptable salt thereof, or a solvate thereof:


37. The compound which is represented by the following formula, or a pharmaceutically acceptable salt thereof, or a solvate thereof:


38. A pharmaceutical composition comprising the compound of any one of claims 36 to 37, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.
 39. A method of inhibiting PDHK in a mammal, comprising administering a pharmaceutically effective amount of the compound of any one of claims 36 to 37, or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal.
 40. A method of inhibiting PDHK2 in a mammal, comprising administering a pharmaceutically effective amount of the compound of any one of claims 36 to 37, or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal.
 41. A method of decreasing the blood glucose level in a mammal, comprising administering a pharmaceutically effective amount of the compound of any one of claims 36 to 37, or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal.
 42. A method of decreasing lactate level in a mammal, comprising administering a pharmaceutically effective amount of the compound of any one of claims 36 to 37, or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal.
 43. A method for the treatment or prophylaxis of diabetes, diabetic complications, insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, brain ischemia, cerebral apoplexy, pulmonary hypertension, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer in mammal, comprising administering a pharmaceutically effective amount of the compound of any one of claims 36 to 37, or a pharmaceutically acceptable salt thereof, or a solvate thereof to the mammal. 